IntechOpen

Home > Books > Current Advances in Amyotrophic Lateral Sclerosis

Open access

Pathophysiology of Amyotrophic Lateral Sclerosis

Written By

Fabian H. Rossi, Maria Clara Franco and Alvaro G. Estevez

Submitted: 09 May 2012 Published: 11 September 2013

DOI: 10.5772/56562

Current Advances in Amyotrophic Lateral Sclerosis IntechOpen
Current Advances in Amyotrophic Lateral Sclerosis Edited by Alvaro Estévez

From the Edited Volume

Current Advances in Amyotrophic Lateral Sclerosis

Edited by Alvaro G. Estévez

Book Details Order Print

Chapter metrics overview

4,104 Chapter Downloads

View Full Metrics
Advertisement

1. Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by death of pyramidal neurons in the motor cortex (upper motor neurons) and motor neurons in the brain stem and central spinal cord (lower motor neurons). This results in muscle weakness, progressive motor disability, and finally death by respiratory failure or an associated infection (Shook and Pioro, 2009). There are two types of ALS familiar (fALS) and sporadic ALS (sALS). They are both clinically undistiguishale one from the other; fALS accounts for 10% of all cases being the rest of the cases sALS (Pasinelli and Brown, 2006). In the last few years, there had been an explosion of genetic studies associating ALS with several genetic mutations in genes codifying for different proteins: Cu/Zn superoxide dismutase, (SOD1), transactive response binding protein 43 (TARDBP), fused in sarcoma (FUS), and valosin containing protein (VCP). Most recently, a genetic defect was identified with an expansion of the noncoding GGGGCC hexanucleotide repeat in the chromosome 9, open reading frame 72 (C9ORF72), associated with ALS with and without frontotemporal dementia (Boeve et al., 2012).

Despite of all these discoveries the etiology of ALS remains elusive. A number of potential pathogenic mechanisms have been associated with ALS including excitotoxicity, mitochondrial dysfunction, apoptosis, glial activation, RNA-processing, growth factor abnormalities, etc. These potential pathogenic processes are reviewed in this chapter.

Advertisement

2. Pathology

ALS is characterized by upper motor neuron (corticospinal motor neurons) and lower motor neuron (bulbospinal motor neurons) degeneration and death as well as reactive gliosis replacing death neurons (Leigh and Garafolo, 1995). As corticospinal motor neuron degenerate the cells suffer from a retrograde axonal loss with secondary myelin pallor and gliosis. These changes are most severed at the brainstem and upper spinal cord, but are extended throughout the spinal cord (Brownell et al., 1970). ALS motor cortex shows astrocytic gliosis, especially in the deeper layers at the gray matter and underlying the subcortical white matter. Irregular immunoreactivity to GFAP is identified in the motor strip (Kamo, et al. 1987; Ince, 2000). The lysosomal marker CD68 also revealed that most of the glial response at the cortical and spinal tracts corresponds to microglia activation and active macrophages (Cagnin et al., 2001; Sitte et al., 2001). ALS affects spinal motor neurons of the ventral horn and brainstem motor neurons. The autopsy of ALS patients shows loss of motor neurons and atrophic motor neurons with basophilic appearance suggesting a programmed cell mechanism (Martin, 1999). The ventral roots become thin with loss of large myelinated fibers in motor nerves leading to denervation atrophy with evidence of reinnervation in affected muscles. Frontal temporal dementia ALS (FTD-ALS) is a neurodegenerative disorder associated with ALS that presents typical pathological findings of the disease in addition to neuronal loss of the frontal or temporal cortex, hippocampus and amygdale, and spongiform changes of the neocortex with (Leigh PN and Garofolo, 1995). Non-motor findings encountered in ALS pathology are posterior columns demyelination and reduced density of myelinated sensory fibers (Ince, 2007)

2.1. Inclusion bodies

The hallmark finding of lower motor neuron (LMN) pathology in ALS is the presence of intracellular inclusion bodies in neuronal soma and proximal dendrites as well as glia (Barbeito et al., 2004).

2.1.1. Ubiquitylated Inclusions (UBI)

UBI are the most common and specific inclusion in ALS, found at LMN of the spinal cord and brainstem (Matsumoto et al., 1993) and also at the corticospinal tract upper motor neurons (UMN) (Sasaki and Maruyama, 1994). UBI morphological spectrum goes from thread-like ubiquitylated profiles, through skeins of different compactness to more spherical bodies (Ince et al, 1998). The compacted lesions may be eosinophilic, basophilic and “Lewy-like” in appearance. The composition of UBI remains unknown but several proteins were identified in UBI such as ubiquitin (Leigh et al., 1991), peripherin (He and Hays, 2004), Cu/Zn SOD1 (Shibata 1996) and dorfin (Niwa et al., 2002). UBI are present in near 100% of sALS (Ince et al., 2003). However, UBI are found in FTD with ubiquitin positive/tau negative inclusions. In both fALS and sporadic types of ALS-FTD, UBI are found in cortical frontal and temporal lobe neurons.

2.1.1.1. TAR DNA binding Protein 43 (TDP-43)

TDP-43 is a major component of ubiquinated inclusions in sALS, FTD with ubiquitin-positive but tau-negative inclusions (non-tau FTD), FTD-ALS, and non-SOD1 fALS. TDP-43 inclusions are practically not present in mSOD1-related fALS.

2.1.1.2. Fused in Sarcoma protein (FUS)

Recently, mutations in the gene codifying for the fused in sarcoma protein (FUS) have been linked to fALS. Indeed, spinal cord LMNs in fALS and sALS but not in mSOD1-fALS are immunoreactive for FUS inclusions. These inclusions also present immunoreactivity for TDP-43 and ubiquitin (Chaudhuri et al., 1995).

2.1.2. Bunina bodies

Bunina bodies are eosinophilic paracrystalline bodies present in the LMNs of many cases of ALS (Piao et al., 2003). They are immunoreactive for a cysteine protease inhibitor called cystatin C (Okamoto et al., 1993).

2.1.3. Hyaline Conglomerate Inclusions (HCI)

HCI consist of intracellular accumulation of intermediate filament proteins, especially hyperphosphorylated neurofilament subunits and peripherin (Corbo and Hays, 2002), and are found in the motor cortex neurons (Troost et al., 1992). HCI are much less frequently encountered in spinal motor neurons than UBI and they are mainly associated with some types of mSOD1 fALS. They form a larger conglomeration than UBI and are positive for silver staining, contrary of UBI. (Ince PG and Wharton S, 2007).

Advertisement

3. Oxidative stress

Mutations in the gene of copper/zinc superoxide dismutase type 1 (SOD1) are the most common cause of fALS (Rothstein, 2009; Boillee and Cleveland, 2008; Robberecht and Phillips, 2013). Recent reports indicate that SOD1 mutations may also be the cause of between 0.7 - 4% cases of sporadic ALS (sALS) (Robberecht and Phillips, 2013). SOD1 is primarily an antioxidant metalloenzyme that catalyzes the conversion of superoxide radical (O2.-) to oxygen (O2) and hydrogen peroxide (H2O2). However, SOD1-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function. One of the hypotheses for mutant SOD-linked fALS toxicity proposes that an aberrant SOD1 chemistry is responsible for the toxic gain-of-function, which allows small molecules such us peroxynitrite or hydrogen peroxide to produce damaging free radicals. Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, and formation of intracellular aggregates. SOD1 aggregation is an early event in ALS and could mediate motor neuron degeneration via sequestration of cellular components, decreasing chaperone activity and the ubiquitin proteasome pathway. Also, SOD1 mutations seem to disrupt RNA processing in the cells.

Defining the role of oxidative stress, and particularly nitrative stress in neurodegeneration has been extremely difficult because of the multiplicity of potential targets that can be damaged by oxidation and nitration. Certain proteins are particularly susceptible to tyrosine nitration by the oxidant peroxynitrite (ONOO-). Tyrosine nitration is a well-established, early biomarker in ALS and it has been proposed that in fALS mutant SOD1 produces motor neuron death by allowing peroxynitrite formation and catalyzing tyrosine nitration, which in turn inhibits trophic signals (Estevez et al., 1999; Beckman et al., 1993; Crow et al., 1997; Ischiropoulos et al., 1992; Franco and Estevez, 2011). Motor neurons are highly dependent on a continuous supply of trophic factors to survive both in vivo and in vitro. Deprivation of trophic support in vivo by ventral root avulsion in adult animals and axotomy in newborns, but not in adults, triggers apoptosis (Li et al, 1994; Oppenheim, 1997; Gould and Oppenheim, 2011). Induction of apoptosis in these conditions is preceded by induction of neuronal nitric oxide synthase (nNOS) and nitric oxide production. Motor neuron death induced by trophic factor deprivation requires protein synthesis and caspase activation both in vivo and in vitro (Milligan et al., 1994; Li et al, 1998; Yaginuma et al, 2001). Cultured motor neurons deprived of trophic factors induce nNOS expression, production of nitric oxide and peroxynitrite formation that is followed by tyrosine nitration, which precedes motor neuron death (Estevez et al., 1998). Inhibition of nitric oxide production and peroxynitrite formation prevents rather than delays motor neuron death, suggesting that peroxynitrite is acting at decision-making points in the apoptotic cascade. Deprivation of trophic factors activates the Fas pathway in motor neurons, and inhibition of the Fas pathway prevents motor neuron death. Fas activation in motor neurons triggers two parallel pathways: the classical extrinsic pathway recruiting FADD and Caspase 8; and a seemingly motor neuron specific pathway, that activates DAXX/ASK1/p38 and the induction of neuronal NOS, increasing production of nitric oxide, peroxynitrite formation and tyrosine nitration (Raoul et al, 2002).

Advertisement

4. Excitotoxicity

4.1. Glutamate

A dominant hypothesis of ALS pathogenesis is glutamate excitotoxicity. Glutamate is the major excitatory neurotransmitter found in mammalian central nervous system (CNS) however, in high concentrations is toxic to motor neurons. Some of the evidence supporting glutamate excitotoxicity was based on the observation that exposure of neuronal cell cultures to excess glutamate leads to cell death (Choi et al 1988). A similar observation was made in anterior horn cells in tissue cultures of rat spinal cord where incubation with high concentrations of glutamate is associated with cell loss (Silani et al 2000). In addition, defects in glutamate transport leading to elevated glutamate levels have been reported in mSOD1 mice and significant number of patients with sALS (Dunlop et al., Lin et al., Rothstein et al.,). Elevated glutamate levels were found in serum and spinal fluid of patients with sALS (Al-Chalabi, et al 2000; Rothstein et al., 1990; Shaw, et al, 1995). Another study showed that 40% of about 400 patients with sALS have an elevation in glutamate levels that correlates with the severity of the disease (Spreux-Varoquax et al., 2002)

The mechanism of glutamate neurotoxicity remains elusive. Excessive glutamate levels lead to activation of glutamate ionotropic AMPA receptors in neurons and glial cells. AMPA receptor activation triggers mitochondrial changes such as reduction in ATP synthesis, decreased cellular oxygen consumption, oxydative phosphorylation uncoupling, and increase in mitochondrial reactive oxygen species (ROS) production, causing a loss in the mitochondrial calcium buffer properties and apotosis (Heath and Shaw 2002) (Fig. 1). Rapid clearance of glutamate at the synapsis cleft is an essential step in the prevention of motor neuron excitotoxicity. This step accomplished by the astrocyte glutamate transporter excitatory amino acid-2 (EAAT2) (Rothstein et,al 1996). In transgenic mice, depletion of EAAT2 has been implicated with neuronal death (Rothstein et,al 1996). Abnormalities in EAAT2 expression were identified in two rodent models of fALS. In the SOD1G85R transgenic mice a ~ 50% decrease in EAAT2 expression was observed in the spinal cord at the end of the disease (Bruijin et al., 1997), while in the spinal cord ventral horn of transgenic SOD1G93A rats EAAT2 expression was decreased before the symptomatic stage of the disease and was almost undetectable at the end of the disease (Howland et al., 2002). Reduction in the expression of EAAT2 was found in motor neuron disease (Fray et al 1998) and decreased glutamate transport was identified in motor cortex and spinal cord in ALS (Rothstein et al., 1992) (Fig. 1).

4.2. Glutamate receptor

An alteration in the expression of the glutamate receptor was found in motor neurons expressing mutant SOD1, suggesting that excitotoxicity is not only induced by increased glutamate levels but also by alterations in the glutamate signaling pathway (Spalloni et al., 2004). In oocytes co-expressing A4V or I113T-SOD1 with EAAT2, the mutants but not the wild type SOD1 selectively inactivated the glial glutamate transporter in the presence of hydrogen peroxide. This suggests that EAAT2 may be a target for mutant SOD1 toxicity (Trotti et al., 1999). On the other hand, overexpression of EAAT2 in mutant SOD1 expressing mice delayed the onset of motor neuron disease and decreased caspase 3 activation, the final step of the apoptotic pathway (Guo et al 2003). In motor cortex and spinal cord extracts from ALS patients, 25% of the patients showed almost complete loss of EAAT2 protein, and 80% of the patients showed some sort of protein abnormality (Rothstein et al., 1995) (Fig.1).

Glutamate receptor dysfunction is other possible route of excitotoxicity. Glutamate toxicity in motor neurons is primarily mediated via alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid (AMPA) receptors (Van Den Bosch et al., 2000). In patients with ALS, a deficiency in the AMPA receptor mRNA expression was found in spinal motor neurons (Kawahara, et al., 2004). This defect results in an increase in calcium influx through the receptor leading to cell damaged. The increased entry in calcium in addition to the reduction in the calcium buffer capacity due to abnormal mitochondria result in an increase in free intracellular calcium levels, leading to motor neuron death (Bogaert et al., 2010) (Fig.1). Additionally, the expression of the glutamate receptor subunits is reduced in ALS motor neurons (Williams et al 1997). Another pathway leading to excitotoxicity is via deficiency in glutamate dehydrogenase activity (Pioro et al., 1999).

The modest protection conferred by the antigluaminergic drug riluzole in ALS patients as well as in mutant SOD1 mice seems to support the effect of glutamate toxicity in the pathogenesis of ALS (Lacomblez et al., 1996; Gurney et al., 1996). However, whether riluzole protects by a mechanism related to its antiglutaminergic properties needs to be established.

Figure 1.

Induction of motor neuron death by glutamate excitotoxicity. Red arrows/lines indicate the pathways that are affected or induced in ALS.

Advertisement

5. Mitochondrial abnormalities

The mitochondrion is a vital organelle with multiple functions within cells. Mitochondria are the main source of ATP, maintain calcium homeostasis and participate in calcium signaling, and play a key role in the intrinsic apoptotic pathway. Mitochondrial malfunction turns motor neuron more vulnerable to damage, especially in aging and stress neurons. Mitochondrial malfunction is an important hypothesis in ALS pathogenesis (Bruijn et al., 2004; Manfredi et al., 2005).

5.1. Mitochondrial morphology

Indeed, mitochondria morphological and ultrastructural changes as well as bioenergetic malfunction have been reported in ALS. SOD1 is localized mainly in the cytoplasm, but has been found also in the mitochondria and other organelles (Okado et al., 2001; Sturtz et al., 2001). Mutant SOD1 protein is present in the mitochondrial intermembrane space, matrix and outer membrane of mitochondria (Higgins, et al, 2002; Vijayvergiya et al., 2005; Vande Velde et al., 2008; Kawamata et al., 2008). This abnormal SOD1 protein may fail to fold properly resulting in mitochondrial protein retention and mitochondrial dysfunction with damaged of the mitochondrial membrane and loss of mitochondrial membrane potential and swelling (Wong et al., 1995; Kong et al., 1998). Severe mitochondrial morphological changes were found in NSC34 cells overexpressing mutant SOD1 (Raimondi et al., 2006; Menzies et al., 2002). In addition, mitochondrial swelling and vacuolization in motor neuron axons and dendrites were reported in mSOD1 mice even before disease onset (Wong et al., 1995; Kong et al., 1998; Borthwick et al., 1999). The presence of abnormal mitochondrial clusters was also described in mutant SOD1 rat motor axons (Sotelo-Silveira et al., 2009) as well as in lumbar spinal cord motor neurons and proximal axons of sALS patients (Sasaki et al., 1996; Hirano et al., 1984).

5.2. Electron transport chain

Abnormal respiratory complex activities, disrupted redox homeostasis and decreased ATP production were described in ALS (Borthwick et al., 1999; Jung et al., 2002; Bowling et al., 1993; Ferri et al., 2006). Biochemical studies showed several abnormalities in mitochondrial electron transport chain. The enzymatic activity of the electron transport chain complexes I, II, IV was reduced in mSOD1 mice and cell cultures from patients with fALS (Jung et al., 2002; Mattiazzi et al., 2002). The interaction between cytochrome c and the inner mitochondrial membrane in addition to the activity of complex IV were reduced in the SOD1G93A transgenic mice (Kirkinezos et al., 2005). Decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential were also reported in mutant SOD1 rat spinal astrocytes (Cassina et al., 2008) (Fig. 2).

5.3. Calcium homeostasis

Mitochondria play an important role in the intracellular calcium homeostasis as a calcium buffer, accumulating or releasing calcium depending on the cytosolic levels. Abnormalities in mitochondrial calcium homeostasis were reported in ALS patients and in mutant SOD1 animals (Kruman et al., 1999; Carri et al., 1997; Reiner et al, 1995; Jaiswal et al., 2009). The release of calcium from the mitochondria leads to excessive intracellular calcium levels. This abnormal calcium homeostasis induces motor neuron death through several mechanisms including: 1) toxic generation of reactive oxygen species (ROS), as reported in SOD1G93A transgenic mice (Kruman et al., 1999); 2) release of cytochrome c from the mitochondria (Martin et al., 2009); 3) glutamate excitotoxicity (Nicholls et al., 2003), and others. All these mechanisms may have a special role in motor neurons because these cells contain less mitochondrial density per volume compared to non-neuronal cells, thus making neurons more deficient in mitochondrial calcium buffering properties (Grosskreutz et al., 2007) (Fig. 2). In addition, ALS patients show a deficiency in calcium binding proteins calbidin and paralbumin in cortical motor and spinal motor neurons. These two proteins regulate intracellular calcium levels and their deficiency may result in neuronal loss. On the contrary, oculomotor neurons or neuron from the Onuff’s nuclei contains normal levels of calbidin and paralbumin levels and they are preserved despite ALS progression (Alexianu, et al. 1994; Celio, 1990; Ince et al., 1993, Palecek et al., 1999).

Figure 2.

Mitochondrial abnormalities associated with mutant SOD1 (mSOD1). Mutant SOD1 translocates to mitochondrial intermembrane space and matrix, and is associated with the mitochondrial outer membrane. The expression of mutant SOD1 is linked to decrease of mitochondrial membrane potential and electron transport chain activity. The release of calcium and cytochrome c to the cytosol, and the production of ROS lead to cell death in ALS.

Advertisement

6. Axonal transport abnormalities

Transport of proteins, vesicles, and organelles between cell body and terminal axons is a vital process in neuronal development, function and survival. Cytoskeletal proteins such as neurofilament (NFs) confer structure and shape to motor neurons, and are involved in axonal anterograde and retrograde transport between soma and motor axons. NFs are intermediate filaments made from the assembly of light, medium, and heavy subunits (Maragakis and Galvez-Jimenez, 2012). Disorganization of NFs affects axonal transport resulting in axonal strangulation and accumulation of axonal cargo (Collard et al., 1995). A hallmark of ALS pathology is the abnormal accumulation of NFs in the neuronal cell bodies and proximal axons. Animal models and patients with ALS show that axonal transport is a critical component in ALS pathogenesis (Morrison et al., 1998; Lin et al., 2006). Transgenic models of fALS and sALS are associated with mutations of the heavy NF subunits (Figlewicz et al., 1994; Al-Chalabi et al., 1999). In addition, reduction in light subunit mRNA levels was found in motor neurons from the spinal cord of patients with ALS (Wong et al., 2000). Abnormal axonal transport, vacuolization and degeneration of axons and motor neurons have been reported in transgenic mice overexpressing or with reduced expression of NF subunits (Collard et al., 1995; Cote et al., 1993). In neurons, mitochondria are frequently found in axon terminals due to the high demand of ATP and calcium handling at the synapses (Shepherd et al., 1998; Rowland et al., 2000). Mitochondria are transported in both anterograde and retrograde directions via kinesin and dynein motor complexes (Nangaku et al., 1994; Zhang, et al 2004; Varadi et al., 2004). The disruption of the mitochondrial axonal transport has been implicated in neurodegenerative diseases including ALS (Hollenbeck et al., 2005; De Vos et al., 2007; Magrane et al. 2009). Mitochondria display saltatory movement along microtubules. In SOD1G93A transgenic mice and cortical neurons transfected with G93A-SOD1, mitochondrial transport was selectively reduced in the anterograde direction (De Vos et al., 2007). In addition, in NSC34 cells overexpressing mutant SOD1 mitochondrial transport was altered in both anterograde and retrograde directions (Magrane et al., 2009). Abnormalities in axonal transport cause abnormal renewal of mitochondria and autophagosomes at distal motor axons resulting in mitochondrial accumulation, deficit in energy production, accumulation of ROS, and released of pro-apoptotic agents leading to neuronal death. Slow axonal transport impairment has been described as one of the earliest pathological events in mSOD1 mice (Williamson et al., 1999; Zhang et al. 1997). Fast axonal transport is mediated by kinesin while dynein motor complexes mediate the transport of membrane-bound organelles necessary for axonal and synaptic functions. In patients and transgenic rodent models of ALS there are impairments in the kinesin-mediated anterograde transport and dynein-mediated retrograde axonal transport (Williamson et al., 1999; Breuer et al 1987; Breuer et al., 1988; Collard et al., 1995; Sasaki et al., 1996; Ligon et al., 2005; Parkhouse et al., 2008). Disruption of kinesin heavy chain KIF5B causes perinuclear clustering of mitochondria in mice neurons, indicating that KIF5B is essential for mitochondrial dispersion (Tanaka et al., 1998). Abnormalities in the transport of other proteins such as dynactin, myosin and actine were also identified in transgenic mutant SOD1 models (LaMonte et al., 2002). Dynactin mutations have been associated with autosomal familiar motor neuron disease (Puls et al 2003; Puls et al 2005). Peripherin, another intermediate transport filament was found in neuronal inclusions of sALS (Corbo et al., 1992). Overexpression of peripherin in transgenic mice is associated with axonal degeneration. Inflammatory cytokines increased peripherin levels, suggesting an association between inflammation and axonal transport disorders (Sterneck, et al 1996).

Advertisement

7. Growth factors

Several growth factors (GFs) has been investigated and potentially implicated in the pathogensis of ALS. One of the most studied GFs is the vascular endothelial growth factor (VEGF), a protein involved in vasculogenesis and angiogenesis, and in restoration of oxygen supply upon limited blood circulation. Animal data suggest that VEGF may be neuroprotector. Overexpression of VEGF delayed onset and progression motor neuron disease, as shown in a double transgenic mice generated by crossing mice expressing human mutant SOD1 with mice overexpressing neuronal VEGF (mSOD1/VEGF). The mSOD1/VEGF transgenic mice showed a delayed in motor neuron loss, motor impairment, and a prolonged survival compared with mutant SOD1 transgenic mice (Wang et al., 2007). Intracerebroventricular administration of VEGF in a SOD1G93A rat model of ALS delayed motor neuron degeneration and onset of paralysis, improved motor performance, preserved neuromuscular junction, and extended survival (Storkebaum et al., 2005). This study also showed that in SOD1G93A mice, neurons expressing a transgenic VEGF receptor prolonged mice survival. Also supporting the VEGF neuroprotective role, a single injection of a VEGF-expressing lentiviral vector into several muscles of SOD1G93A mice delayed the onset as well as the progression of the disease even at onset of paralysis (Azzouz et al., 2004). Interestingly, mouse models in which the hypoxia-response element in the VEGF gene was deleted showed a decrease in VEGF expression in normoxia and under hypoxic conditions. This model resulted in a progressive motor neuron degeneration disease that resembles ALS (Oosthuyse, et al., 2001). A meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England with a specific haplotype for VEGF associated with reduced circulating VEGF and VEGF gene transciption showed a two-fold increase in the risk of developing ALS for these individuals (Lambrechts et al., 2003). In another study, SOD1G93A mice crossed with VEGF haplotype mice showed a much more severe motor neuron degeneration. VEGF probably has neuronal direct and indirect neuroprotective effects preventing ischemic changes while regulating vascular perfusion.

Additionally, VEGF-B, a homolog of VEGF with minimal angiogenetic activity, was shown to be protective for cultured primary motor neurons. In addition, transgenic mice with deletion of the VEGF-B gene were implicated in an ALS-like pathogenesis, as shown crossing a VEGF-B knockout mouse with transgenic mice expressing human mutant SOD1 (mSOD1/VEGF-B-/-) (Poesen et al., 2008). mSOD1/VEGF-B-/- mice showed an earlier death and more severe motor neuron degeneration compared with mutant SOD1 transgenic mice. Intracerebroventricular administration of VEGF-B in a SOD1G93A rat model of ALS prolonged the survival of mutant SOD-expressing rats, suggesting that VEGF is neuroprotective by a mechanism independent of angiogenesis (Poesen et al., 2008).

Other beneficial growth factors are innsuline growth factor-1, glial cell line –derived neurotrophic factor, and brain derived neurotrophic factor.

Advertisement

8. RNA metabolism disorders

Ubiquinated intracytoplamsmatic inclusions containing trans-activation response DNA-binding protein of 43 KDa (TDP-43), encoded by the TARDBP gene in chromosome-1, had been identified in motor neurons of patients with sALS and frontal lobar degeneration (FTLD) linked to TDP-43 pathology (FTLD-TDP) (Neumann et al., 2006). TDP-43 positive inclusions were also identified in patients with non-SOD1 fALS. Gene mutations of the TDP-43 gene probably accounts for 5% of patients with fALS. All the cases of sALS and SOD1 negative fALS have neural and glial inclusions immunoreactive to both ubiquitin and TDP-43 whereas positive SOD1 mutations in fALS were absent of TDP-43 immunoreactivity. (MacKenzie et al., 2007; Tran et al., 2007). TDP-43 inclusions were also identified in patients with Guamanian parkinsonism-dementia complex, and familial British dementia (Sreedharan et al., 2008; Kabashi et al., 2008; Van Deerlin et al., 2008; Yokoseki et al., 2008; Rutherford et al., 2008; Del Bo et al., 2009; Hasegawa et al., 2007; Schwab et al., 2009). TDP-43 is a nuclear protein expressed in almost all tissues that binds to mRNA and DNA and regulates mRNA processing processes such as splicing, translation, and gene transcription. TDP-43 structure consists of two RNA recognition motifs (RRMs) that bind to nucleic acids, and a glycine rich domain containing the majority of ALS associated mutations (Cohen et al., 2012; Buratti et al., 2001). Genetic mutation of another RNA processing protein, fused in sarcoma /translated in liposarcoma (FUS/TLS), has been also associated with ALS (Kwiatkowski et al., 2009; Vance et al., 2009). The FUS/TLS has a similar structure to TDP-43 with RRM and glycin rich domains. FUS/TLS, also a nuclear protein, accumulates in intracytoplasmatic tau- and TDP-43 negative inclusions in patients with fALS, sALS, and frontal lobar degeneration FTLD-FUS (Mackenzie et al., 2010). TDP-43 and FUS/TLS stabilized mRNA encoding histone deacetylase 6 (HDAC6) involved in clearance of misfolded protein aggregates (Kim et.al, 2010, Fiesel, et al., 2010; Lee et al., 2010; Kawaguchi et al., 2003). TDP-43 binds to a wide range of RNA targets and promotes the synthesis of several proteins implicated in the neuronal development and integrity (Tollervey et al., 2011). TDP-43 expression is carefully controlled by a tightly autoregulated mechanism (Winton et al., 2008). Thus, TDP-43 abnormalities in RNA binding and autoregulation, and FUS/TLS may have a essential role in neuronal integrity. TDP-43 also has a protective effect on mitochondrial function; abnormal expression of mitochondrial fission/fusion proteins in transgenic mice expressing human wild-type TDP-43 transgene driven by mouse prion promoter had been reported (Xu et al., 2010). In cultured cells, exposure to stress caused TDP-43 to be relocated into stress granules (SGs). This abnormal localization of TDP-43 could start a pathological TDP-43 aggregation or TDP-43 interaction with other SGs-proteins. A similar process may occur with FUS/TLS protein (Bosco et al., 2010; Dormann et al., 2010). The formation of SGs may lead to pathological inclusion aggregations resulting in neuronal and glial cell damage. Hyperphosphorilated TDP-43 aggregates were identified in ALS spinal cord and FTLP-TDP brain tissue. TDP-43 glycin-rich domain, where most of the mutations had been identified, seems to be required for TDP-43 association with SGs. Expression of insoluble aggregates of TDP-43 terminal fragment was implicated in the generation of SGs (Liu-Yesucevitz et al., 2010). In addition, TDP-43 interacts with cytoplasmatic Ataxin-2 protein resulting in TDP-43 accumulation in misfolded aggregates. Mutant polyglutamine expansions within ataxin-2 enhanced the binding to TDP-43 facilitating the formation of aggregates in ALS patients (Elden,AC et al., 2010). The formation of these aggregates seems to be implicated in neuronal death, but the mechanism remains elusive.

Advertisement

9. Non-cell autonomous mechanisms

Evidence is accumulating indicating that motor neuron degeneration in ALS is not only restricted to neuronal autonomous cell death but it is rather a more complex process involving inflammatory neurotoxicity from non-neuronal glial cells such as astrocytes and microglia (Phani et al., 2012). Support for non-autonomous evidence comes from several studies in transgenic mutant SOD1 mice. The expression of mutant SOD1 restricted to motor neurons in vivo was not enough or caused a mild neurodegeneration (Jaarsma et. al.; 2008). Indeed, when mutant SOD1 expression was reduced in microglia and macrophages there was a reduction in motor neuron degeneration (Boillee 2006, Wang 2009). In addition, mutant SOD1 expression in astrocytes is required to cause neurodegeneration by release of toxic factors (Gong et. al., 2000; Nagai et al. 2007). Co-cultures of healthy motor neurons with astrocytes expressing mutant SOD1 resulted in more than 50% motor neuron death (Marchetto et al, 2008), while astrocytes obtained from postmortem tissue from patients with fALS and sALS were both toxic to motor neurons (Haidet-Phillips et al., 2011). In agreement, mutant SOD1 knockdown in astrocytes attenuated toxicity towards motor neurons, suggesting that the mutant enzyme plays a role in both fALS and sALS (Phillips et al., 2011). SOD1G93A glial-restricted precursor cells transpanted into the cervical spinal cord of wild type rats survived and differentiated efficiently into astrocytes. These graft-derived SOD1G93A astrocytes induced host ubiquitination and death of motor neurons, reactive astrocytosis, and reduction of the glial glutamate transporter GLT-1 expression that was associated with animal limb weakness and respiratory dysfunction (Papadeas et al., 2011). The SOD1G93A astrocyte-induced motor neuron death may be madiated by host microglial activation (Papadeas et al., 2011).

Abnormalities in the immune system have also been observed in ALS patients. Blood samples of ALS patients have increased levels of CD4+ cells and reduced levels of CD8+ T lymphocytes. However, early in the disease when motor features are still mild there is a reduction in CD4+/CD25+ T-regulatory cells (T-reg) and CD14+ monocytes. These observations suggest that the reduction in circulating T-reg cells could be due to the relocation of the cells into the central nervous system. Upon relocation, the T-reg cells would activate the innate immune cells like microglia, leading to the release of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-β to protect the affected area (Kipnis et al., 2004 and Mantonavi, et al., 2009). Indeed, immunostaining for the astrocytic marker glial fibrillary acid protein (GFAP) showed a significantly increased presence of astrocytes in the precentral gyrus of patients with both fALS and sALS. In addition, staining for activated microglia and macrophages markers such as leukocyte common antigen (LCA), lymphocytes function associate molecule (LFA-1), complementary receptors CR3 (CD11b), and CR4 (CD11c) was also increased in motor cortex, brainstem, and corticospinal tract (Kawamata, et al., 1992; Papidimitriou et al., 2010). Samples from brain and spinal cord from animal models and patient with ALS also showed a significant increase in activated or reactive astrocytes, an indication of neuroinflammation (Sta et al., 2011).

Astrocytes and microglia play an essential role in immune surveillance and response in the central nervous system. Reactive astrocytes recruited to the injured area reestablish the blood-brain-barrier (BBB), release neurotrophins and growth factors (IGF-1), clear debri, and isolate the injured region through the formation of a glial scar (Papadimitriou et al 2010; Dong and Benviste 2001). Microglia are also activated in the presence of antigens exposed during neurodegeneration leading to the phagocytosis of cellular debri and the secretion of several neurotrophic factors, neurotrophins, and cytokines. However, a poor regulation of these factors could be harmful to motor neurons. Microglia seems to protect motor neurons from neurodegeneration, but is activated in the first steps of neurodegeneration. An increase in the immunostaining for GFAP and CD11 suggests the presence of reactive astrocytes and microglia in SOD1 transgenic mice (Fischer et. al, 2004). Increase in NGF, a sign of reactive atrocytes, leads to aptoptosis in ALS through a pathway involving activation of p75 (Pehar et al., 2004). Additionally, in ALS animal models mutant SOD1-expressing astrocytes are neurotoxic to motor neurons, and reducing mutant SOD1 expression decreases motor neuron degeneration and increases animal life span (Lepore at al., 2008, Barbeito et al., 2010). The release of pro-inflammatory cytokines, oxidative stressors such as prostanglandins, leukotrienes, and reactive nitrogen species (RNS) is toxic to motor neurons (Henkel, et al., 2009). In in vitro studies, normal motor neurons die through a pro-apoptotic Bax pathway when co-cultured with astrocytes expressing mutant SOD1 (Nagai at al., 2007). In in vivo studies, microglia releases pro-inflammatory cytokines such us TNF-α and IL-1β as well as ROS (Henkel 2009) whereas in ALS patients, there is an increase of pro-inflammatory cytokines and prostranglandin E2 (Papadimitou, 2010). Media obtained from activated microglia causes motor neuron death by activation of TNF-α and NMDA receptors (Moisee and Strong 2006). In mouse model of ALS, a reduction in the expression of mutant SOD1 by microglia does not change age of symptoms onset, but slowed down disease progression (Boillee et al. 2006b). Motor neurons expressing mutant SOD1 are more susceptible to Fas ligand and NO-triggered cell death (Raoul et al., 2002), suggesting that in the context of ALS progression, motor neurons expressing mutant SOD1 are more vulnerable to external stimuli such as ROS, RNS and toxic factors release by surrounding cells.

Advertisement

10. Apoptosis

Apoptosis is a programmed cell death cascade involved in several physiological processes during development and aging. Cell death by apoptosis sustains the homeostasis of cell population in tissues including cell turnover, hormone dependent- and chemical induced-cell death, and immune system development. The programmed cell death also functions as a defense when cells are damaged by disease or noxious stimuli (Elmore, S; 2007). Thereby, inappropriate apoptosis is a potential mechanism implicated in the pathogenesis of several neurodegenerative disorders, including ALS (Elmore, S; 2007). There are two main apoptotic pathways, the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway (Igney and Krammer, 2002). The extrinsic pathway involves transmembrane receptor-mediated interactions between ligands and death receptors resulting in transmission of death signals from cell surface to the intracellular signaling pathways (Locksley et al., 2001). The most studied ligand and death receptor association are Fas ligand and Fas receptor (FasL/FasR) and tumor necrosis factor (TNF) and its receptor (TNFL/TNFR) (Hsu et al 1995; Wajant, 2002). The intrinsic pathway consists of non-receptor-mediated stimuli that cause changes in the inner mitochondrial membrane. These changes include the opening of mitochondrial membrane pores leading to loss of transmembrane potential and released of pro-apoptotic proteins such as cytochrome c, Smac/DIABLO, HtrA2/Omi, and others ending with the activation of caspases (Sealens, et al., 2004; Du et al., 2000; Van Loo et al., 2002; Garrido at al., 2005). The Bcl-2 family of proteins regulates the intrinsic apoptotic pathway (Cory and Adams 2002) and these proteins in turn are regulated by the tumor suppressor protein p53 (Schuler and Green, 2001). The Bcl-2 family includes pro-apoptotic and anti-apoptotic proteins. Some of the anti-apoptotic proteins comprise Bcl2, Bcl-x, Bcl XL, Bcl-XS, Bcl-w, BAG, whereas the pro-apoptotic proteins include Bcl-10, BAX, Balk, Bid, Bad, Bim, Bik, and Blk. Both the intrinsic and extrinsic pathways require a specific stimuli to activate its own caspase initiator (caspase -2,-8,-9,-10). These two pathways, once activated, convey in the activation of a final execution pathway with cleavage of caspase-3, resulting in DNA fragmentation, cytoskeletal and nuclear protein cleavage, protein cross-linking, apoptotic bodies formation, expression of ligands for phagocytic recognizion, and final uptake by phagocytic cells (Martinvalet, et al, 2005). There is compelling evidence in ALS, at least in mutant SOD1-ALS, that toxicity is mediated by apoptosis. In transgenic SOD1 mice there are numerous apoptotic findings such as DNA fragmentation, caspase activation, and altered expression of the anti-apoptotic protein Bcl-2 (Durham HD, et al. 1997; Spooren WP et al. 2000). Motor neuron degeneration in ALS structurally resembles apoptosis. The neuronal death progression is divided in 3 sequential stages: chromatolysis, somatodendritic attrition, and apoptosis. In ALS, in the spinal cord anterior horn and motor cortex there is DNA fragmentation and increased in caspase-3 activity. Vulnerable central nervous system regions affected by ALS show elevation of pro-apoptotic proteins Bax and Bak and reduction of the antiapoptotic protein Bcl-2 in mitochondrial-enriched membrane compartment. Co-immunoprecipitation experiments show greater Bax-Bax interactions and lower Bax-Bcl-2 interactions in the mitochondrial-enriched membrane compartment of ALS motor cortex compared with controls, (Martin LJ, 1999). In mutant SOD1 mice apoptotic signals are activated in sequence, caspase 1, an inflammatory caspase, is activated at disease onset while activated caspase-3 is detected later in the curse of the disease (Pasinelli, P, et al. 2000). In SOD1 mice, intracerebroventricular injection of a broad caspase-inhibitor reduces caspase 1 and caspase 3 mRNA levels resulting in spear motor neurons at the spinal cord and delay in disease onset and progression compared with vehicle-infused mice (Li M, et al.; 2000). Overexpression of the antiapoptotic protein Bcl-2 and deletion of the pro-apoptotic protein Bax preserve motor function and prolong life in a SOD1G93A model. Genetic deletion of mitochondrial pro-apoptotic Bak and Bax proteins in a mouse model of ALS prevent neuronal loss and axonal degeneration, and delayed onset of disease (Reyes et al., 2012).

In SOD1G93A transgenic mice, cytosolic release of cytochrome c was observed (Pasinelli, et al., 2004; Kirkinezos et al., 2005; Takeuchi et al., 2002), and levels of pro-apoptotic proteins Bad and Bax were increased while those of anti-apoptotic proteins Bcl2, Bcl-xL and XIAP were decreased (Guegan et al., 2001; Vukosavic et al., 1999; Ishigaki et al., 2002). Caspase 1 and caspase 3 were also sequentially activated in motor neurons and astrocytes in SOD1G93A, SOD1G37R, and SOD1G85R mice (Li et al., 2000; Pasinelli et al., 1998; Pasinelli et al., 2000). Intraventricular administration of minocycline, which inhibits cytochrome c release from mitochondria, was shown to delay disease onset and extend survival (Zhu et al., 2002). However minocycline failed in human ALS patients (Gordon et al, 2007). Similar results were observed upon intraventricular administration of the broad-spectrum caspase inhibitor zVAD-fmk (Li et al., 2000). Additionally, over-expression of anti-apoptotic protein Bcl-2 delayed activation of the caspases, attenuated neuron degeneration and delayed disease onset and mortality (Vukosavic et al., 1999, Kostic et al., 1997).

11. Conclusion

The research in the ALS field encounters many limitations, what is clearly reflected in the little progress accomplished in the therapy of this neurodegenerative disorder. Most of the studies describe the mechanisms involved in the pathogenesis of the familial form of ALS, which accounts for a minority of all the ALS cases. However, some of the hypothesis currently under investigation may also explain how the pathology develops in the sporadic forms of ALS. In the last two decades several experimental models in vitro and in vivo have shaded light into the pathogenesis of the disease. Several potential mechanisms have been implicated in ALS onset and progression including oxidative stress, excitotoxicity, mitochondrial dysfunction, glial activation, RNA-processing, and growth factor abnormalities. Whether these mechanisms intertwine, work in parallel or in sequence to cause neuronal death remains to be investigated.

References

  1. 1. Al-chalabiAAndersenP. MNilssonPChiozaBAnderssonJ. LRussCShawC. EPowellJ. Fand LeighP. NDeletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet 1999
  2. 2. Al-chalabiALeighP. N2000Recent advances in amyotrophic lateral sclerosis. Current Opinion in Neurology; 134397405
  3. 3. AlexianuM. EHoB. KMohamedA. HLa Bella V, Apple SH. The role of calcium-binding protein in selective motor neuron vulnerability in Amyotrophic Lateral Sclerosis. Annals of Neurology 1994
  4. 4. ArisatoTOkuboRArataHAbeKFukadaKSakodaSShimizuAQinX. HIzumoSOsameMNakagawaMClinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families. Acta Neuropathol 2003
  5. 5. BarbeitoA. GMesciPBoileeS2010Motor neuron-immune interactions: the vicious circle of ALS. J. Neural Transm.; 1179811000
  6. 6. BarbeitoL. HPeharMCassinaPVargasM. RPeluffoHVieraLEstévezA. GBeckmanJ. S2004A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Brain Res Rev.; 47(1-3):263-74.
  7. 7. BeckmanJ. SMCarsonC. DSmithand W. HKoppenol1993ALS, SOD and peroxynitrite. Nature 364:584.
  8. 8. BoeveB. FBoylanK. BGraff-radfordN. RDejesus-hernandezMKnopmanD. SPedrazaOVemuriPJonesDLoweVMurrayM. EDicksonD. WJosephsK. ARushB. KMachuldaM. MFieldsJ. AFermanT. JBakerMRutherfordN. JAdamsonJWszolekZ. KAdeliASavicaRBootBKuntzK. MGavrilovaRReevesAWhitwellJKantarciKJack CR Jr, Parisi JE, Lucas JA, Petersen RC, Rademakers R. 2012Characterization of frontotemporal dementia and/or amyortrophic lateral sclerosis associated with the GGGGcc repeat expansion in C9ORF72. Brain.; 1353765783
  9. 9. BogaertEdYdewalleCVan DenBosch L. 2010Amyotrophic lateral sclerosis and excitotoxicity: from pathological mechanism to therapeutic target. CNS Neurol Disord Drug Targets Jul; 93297304
  10. 10. BoilléeSYamanakaKLobsigerC. SCopelandN. GJenkinsN. AKassiotisGKolliasGClevelandD. W2006Onset and progression in inherited ALS determined by motor neurons and microglia. Science; 31213891392
  11. 11. BoilleeSand ClevelandD. W2008Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1. J Clin Invest 118474478
  12. 12. BorthwickG. MJohnsonM. AInceP. GShawP. JTurnbullD. M1999Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol.; 46787790
  13. 13. BoscoD. ALemayNKoH. KZhouHBurkeCKwiatkowski TJ Jr, Sapp P, McKenna-Yasek D, Brown RH Jr, Hayward LJ. 2010Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum. Mol. Genet. 1941604175
  14. 14. BowlingA. CSchulzJ. BBrownR. HJr., Beal MF. 1993Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem.; 6123222325
  15. 15. BreuerA. CAtkinsonM. B1988Fast axonal transport alterations in amyotrophic lateral sclerosis (ALS) and in parathyroid hormone (PTH)-treated axons. Cell Motil Cytoskeleton; 10321330
  16. 16. BreuerA. CLynnM. PAtkinsonM. BChouS. MWilbournA. JMarksK. ECulverJ. EFleeglerE. J1987Fast axonal transport in amyotrophic lateral sclerosis: an intra-axonal organelle traffic analysis. Neurology; 37738748
  17. 17. Brownell B Oppenheimer DRHughes JT. 1970The central nervous system in the motor neuron disease. J Neurol Neurosurg Psychiatry; 33338357
  18. 18. BruijinL. IBecherM. WLeeM. K1997ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1 containing inclusions. Neuron; 18327338
  19. 19. BruijnL. IMillerT. MClevelandD. W2004Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci.; 27723749
  20. 20. BurattiEand BaralleF. E2001Characterization and functional implicatios of the RNA binding properties of the nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J. Biol. Chem.; 2763633736343
  21. 21. CagninABrooksD. JKennedyA. MGunnR. NMyersRTurkheimerF. EJonesTBanatiR. B2001In vivo measurement of activated microglia in dementia. Lancet 358461467
  22. 22. CarriM. TFerriABattistoniAFamhyLGabbianelliRPocciaFRotilioG1997Expression of a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells. FEBS Lett.; 414365368
  23. 23. CassinaPCassinaAPeharMCastellanosRGandelmanMDe LeonARadiR2008Mitochondrial dysfunstion in SODG93A-bearing astrocyres promoters motor neuron degeneration: prevention of mitochondrial target antioxidants. J Neurosci.; (28)16:4115-4122.
  24. 24. CelioM. R1990CalbidinDK and Parvalbumin in the rat nervous system. Neuroscience; (35)2:375-475
  25. 25. ChoiD. WKohJand PetersS1988Pharmacology of glutamate neurotoxicity in cortical cell cultures: attenuation by NMDA antagonists. J. Neurosci., 8185196
  26. 26. CohenT. JLee VMY, and Trojanowski Q. 2011TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends In Molecular Medicine; 1711659667
  27. 27. CollardJ. FCoteFJulienJ. P1995Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature; 3756164
  28. 28. CorboMHaysA. P1992Peripherin and neurofilament protein coexist in spinal spheroids of motor neuron disease. J. Neuropathol Exp Neurol 5155317
  29. 29. CorySAdamsJ. M2002The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 264756
  30. 30. CôtéFCollardJ. FJulienJ. P1993Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell; 73:35.
  31. 31. CrowJ. PM. JStrongYZhuangYYeand J. SBeckman1997bSuperoxide dimutase catalyzes nitration of tyrosines by peroxinitrite in the rod and head domains of neurofilament L. J Neurochem 6919451953
  32. 32. DamianoMStarkovA. APetriSKipianiKKiaeiMMattiazziMFlint Beal M, Manfredi G. 2006Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J Neurochem.; 9613491361
  33. 33. De VosK. JChapmanA. LTennantM. EManserCTudorE. LLauK. FBrownleesJAckerleySShawP. JMcloughlinD. MShawC. ELeighP. NMillerC. CGriersonA. J2007Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet.;1627202728
  34. 34. Del Bo RGhezzi S, Corti S, Pandolfo M, Ranieri M, Santoro D, Ghione I, Prelle A, Orsetti V, Mancuso M, Sorarù G, Briani C, Angelini C, Siciliano G, Bresolin N, Comi GP.2009TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. Eur J Neurol.166727732
  35. 35. DongYand E. NBenveniste2001Immune function of astrocytes. Glia; 36180190
  36. 36. DormannDRoddeREdbauerDBentmannEFischerIHruschaAThanM. EMackenzieI. RCapellASchmidBNeumannMHaassC2010ALS- associated fused in sarcoma (FUS) mutation disrupt Transportin-mediated nuclear import. EMBO J. 2928412857
  37. 37. DuCMFangYLiLLiXWang2000Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell; 1023342
  38. 38. DunlopJBeal McIlvain H, She Y, Howland DS. 2003Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. J Neurosci; 23:1688.
  39. 39. DurhamH. DRoyJDongLFiglewiczD. A1997Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol; 56:523.
  40. 40. EldenA. CKimH. JHartM. PChen-plotkinA. SJohnsonB. SFangXArmakolaMGeserFGreeneRLuM. MPadmanabhanAClay-falconeDMccluskeyLElmanLJuhrDGruberP. JRübUAuburgerGTrojanowskiJ. QLeeV. MVan DeerlinV. MBoniniN. MGitlerA. D2010Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466. 10691075
  41. 41. ElmoreS2007Apoptosis: a review of Programmed Cell Death. Toxicol Pathol. 354495516
  42. 42. EstévezA. GSpearNManuelS. MBarbeitoLRadiRBeckmanJ. S1998Role of endogenous nitric oxide and peroxinitrite formation in the survival and death of motor neurons in culture. Progress in Brain Research; 118269280
  43. 43. EstévezA. GJ. PCrowJ. BSampsonCReiterZhuangY. XRichardsonG. JTarpeyM. MBarbeitoLBeckmanJ. S1999Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 28624982500
  44. 44. FerriACozzolinoMCrosioCNenciniMCasciatiAGrallaE. BRotilioGValentineJ. SCarriM. TFamilial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. 2006Proc Natl Acad Sci U S A.; 1031386013865
  45. 45. FieselF. CVoigtAWeberS. SVan den Haute C, Waldenmaier A, Görner K, Walter M, Anderson ML, Kern JV, Rasse TM, Schmidt T, Springer W, Kirchner R, Bonin M, Neumann M, Baekelandt V, Alunni-Fabbroni M, Schulz JB, Kahle PJ. 2010Knockdown of transactive response DNA-binding protein (TDP-43) downregulate histone deacetylase 6. EMBO J. 29209221
  46. 46. Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien JP. 1994. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet 3:1757-1761.
  47. 47. FischerL. RCulverD. GTennantPDavisA. AWangMCastellano-sanchezAKhanJPolakM. AGlassJ. D2004Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185232240
  48. 48. GeserFMartinez-lageMRobinsonJUryuKNeumannMBrandmeirN. JXieS. XKwongL. KElmanLMccluskeyLClarkC. MMalundaJMillerB. LZimmermanE. AQianJVan DeerlinVGrossmanMLeeV. MTrojanowskiJ. Q2009Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol. 6621809
  49. 49. GhatakN. RCampbellW. WLippmanR. HHadfieldM. G1986Anterior horn changes of motor neuron disease associated with demyelinating radiculopathy. J Neuropathol Exp Neurol Jul;45438595
  50. 50. GongY. HParsadanianA. SAndreevaASniderW. DElliottJ. L2000Resticted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does cause motor neuron degeneration. J Neurosci 20660665
  51. 51. GouldT. Wand OppenheimR. W2011Motor neuron trophic factors: therapeutic use in ALS? Brain Res Rev 67139
  52. 52. Gordon P.H., D.H.Moore, R.G. Miller, J.M. Florence, J.L. Verheijde, C. Doorish, J.F. Hilton, G.M. Spitalny, R.B. MacArthur, H. Mitsumoto, H.E. Neville, K. Boylan, T. Mozaffar, J.M. Belsh, J. Ravits, R.S. Bedlack, M.C. Grave, L.F. McCluskey, R.J. Barohn, R. Tandan. 2007. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol.6:1045-1053.
  53. 53. GrosskreutzJHaaztertKDewilMVan DammePCalleweartGvan Den Bosh. 2007Role of mitochondria in kainate induced fast calcium transient in culture of spinal motor neurons. Cell Calcium; (42)1:56-59.
  54. 54. GueganCMVilaGRosoklijaA. PHaysSPrzedborski2001Recruitment of the mitochondrial-dependent apoptotic pathway inamyotrophic lateral sclerosis. J Neurosci. 2165696576
  55. 55. GuoHLaiLButchbachM. E2003Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset of but not the outcome of ALS in mice. Hum Mol Genet; 1221192532
  56. 56. GurneyM. ECuttingF. BZhaiPDobleATaylorC. PAndrusP. KHallE. D1996Benefit of vitamin E, riluzole, and gabapentin in the transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol; 39147157
  57. 57. Haidet-phillipsA. MM. EHesterC. JMirandaKMeyerLBraunAFrakesSSongSLikhiteM. JMurthaK. DFoustMRaoAEagleAKammesheidtAChristensenJ. RMendellA. HBurghesand B. KKaspar2011Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nature biotechnology 29824828
  58. 58. HasegawaMAraiTAkiyamaHNonakaTMoriHHashimotoTYamazakiMOyanagiK2007TDP-43 is deposited in the Guam parkinsonism- dementia complex brains. Brain. 13013861394
  59. 59. HeC. ZHaysA. P2004Expression of peripherin in ubiquinated inclusions of amyotrophic lateral sclerosis. J Neurol Sci 15;21714754
  60. 60. Heath and Shaw2002Update on the glutaminergic neurotransmitter system and the role of excitotoxicity in amyothrophic lateral sclerosis Muscle Nerve; 26438458
  61. 61. HenkelJ. SD. RBeersWZhaoand S. HAppel2009Microglia in ALS: the good, the bad, and the resting. J. Neiroimmune Pharmacol. 4389398
  62. 62. HigginsC. MJungCDingHXuZ2002Mutant Cu, Zn superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J Neurosci.; 22:RC215.
  63. 63. HiranoANakanoIKurlandL. TMulderD. WHolleyP. WSaccomannoG1984Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis. J Neuropathol Exp Neurol.; 43471480
  64. 64. HollenbeckP. JSaxtonW. M2005The axonal transport of mitochondria. J Cell Sci.; 11854115419
  65. 65. HowlandD. SLiuJSheY2002Focal loss of the glutamate transporter EAAT2 in transgenic rat model of SOD1 mutant mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA; 9916041609
  66. 66. HsuHJXiongD. VGoeddel1995The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 81495504
  67. 67. HughesJ. T1982Pathology of amyotrophic lateral sclerosis. Adv Neurol.; 366174
  68. 68. IgneyF. HP. HKrammer2002Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 227788
  69. 69. InceG. Iand WhartonS. BCytopathology of motor neuron. Handbook of clinical neurology. Eisen AA and Shaw PJ (eds.) Elesevier 89119
  70. 70. IncePStoutNShawPSladeJHunzikerWHeizmanC. WBainbridgeK. G1993Parvalbumine and Calbidin D-28 K in human motor system and in motor neuron disease. Neuropathology and Applied Neurobiology (19)4:291-299.
  71. 71. Ince PG Evans JKnopp M. 2003Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology; 6015251258
  72. 72. InceP. GNeuroapthology. In Brown RJ, Meininger V, Swash M (eds) Amyotrophic lateral sclerosis. Martin Dunitz, London, 83112
  73. 73. IschiropoulosHLZhuJChenMTsaiJ. CMartinC. DSmithand J. SBeckman1992Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Archives of Biochemistry and Biophysics 298431437
  74. 74. IshigakiSYLiangMYamamotoJNiwaYAndoTYoshiharaHTakeuchiMDoyuGSobue2002X-Linked inhibitor of apoptosis protein is involved in mutant SOD1-mediated neuronal degeneration. J Neurochem. 82576584
  75. 75. JaarsmaDETeulingEHaasdijket al2008Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J. Neurosci. 2820752088
  76. 76. JaiswalM. KZechW. DGoosMLeutbecherCFerriAZippeliusACarriM. TNauRKellerB. U2009Impairment of mitochondrial calcium handling in a mtSOD1 cell culture model of motoneuron disease. BMC Neurosci.; 10:64.
  77. 77. JungCHigginsC. MXuZ2002A quantitative histochemical assay for activities of mitochondrial electron transport chain complexes in mouse spinal cord sections. J Neurosci Methods.; 114165172
  78. 78. KabashiEValdmanisP. NDionPSpiegelmanDMcconkeyB. JVande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA. 2008TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 405572574
  79. 79. KamoHHaebaraHAkiguchiMet al1987A distinctive pattern of reactive gliosis in the precental cortex in amyothophic lateral sclerosis. Acta Neuropathol 743338
  80. 80. KawaguchiYKovacsJ. JMclaurinAVanceJ. MItoAYaoT. P2003The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell; 115727738
  81. 81. KawaharaYItoKSunHAizawaHKanazawaIKwakS2004Glutamate receptors: RNA editing and death of motor neurons. Nature 427 (6977): 801.
  82. 82. KawamataHManfrediG2008Different regulation of wild-type and mutant Cu,Zn superoxide dismutase localization in mammalian mitochondria. Hum Mol Genet.; 1733033317
  83. 83. KawamataTAkiyamaHYamadaTMc GreerP. L1992Immunologic reaction in amyotrophic lateral sclerosis brain and spinal cord tissue. Am. J. Pathol. 140691707
  84. 84. KimS. HShanwareN. PBowlerM. JTibbettsR. S2010Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in common biochemical complex to co-regulate HDAC6 mRNA. J. Biol. Chem. 2853409734105
  85. 85. KirkinezosI. GBacmanS. RHernandezDOca-cossioJAriasLMoralesC. T2005Cytochrome c association with the inner mitochondria membrane is impaired in central nervous system of G93ASOD1 mice. J Neurosci (25)1:164-172.
  86. 86. KobayashiSIshigakiMDoyuGSobue. 2002Mitochondrial localization of mutant superoxide dismutase 1 triggers caspase-dependent cell death in a cellular model of familia amyotrophic lateral sclerosis. J Biol Chem. 2775096650972
  87. 87. KongJXuZ1998Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci.; 1832413250
  88. 88. KosticVVJackson-lewisFDe BilbaoMDubois-dauphinSPrzedborski1997Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science. 277559562
  89. 89. KrumanI. IPedersenW. ASpringerJ. EMattsonM. P1999ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. Exp Neurol.; 1602839
  90. 90. Kwiatkowski TJ JrBosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr. 2009Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 323591812051208
  91. 91. LacomblezLBensimonGLeighP. NGuilletPMainingerVDose-ranging study of riluzole in Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 34714251431
  92. 92. LaMonte BHWallace KE, Holloway BA, Shelly SS, Ascaño J, Tokito M, Van Winkle T, Howland DS, Holzbaur EL. 2002Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34715727
  93. 93. LeporeA. CRauckBDejeaCPardoA. CRaoM. SRothsteinJ. DMaragakisN. J2008Focal transplantation of astrocytes replacement is neuroprotective in a model of motor neuron disease. Nat. Neurosci. 1112941301
  94. 94. LeeJ. YNaganoYTaylorJ. PLimK. LYaoT. P2010Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J. Cell Biol. 189671679
  95. 95. LeighP. Nand OGarofolo1995The molecular pathology of motor neurone disease. In Motor neurone disease. M. Swash and P.N. Leigh, editors. Springer Verlag, London. 139161
  96. 96. LiLPrevetteDOppenheimR. Wand MilliganC. E1998Involvement of specific caspases in motoneuron cell death in vivo and in vitro following trophic factor deprivation. Mol Cell Neurosci 12157167
  97. 97. LiLOppenheimR. WLeiMand HouenouL. J1994Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse. J Neurobiol 25759766
  98. 98. LiMV. OOnaCGueganMChenVJackson-lewisL. JAndrewsA. JOlszewskiP. EStiegJ. PLeeSPrzedborskiFriedlanderR. M2000Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 288335339
  99. 99. LiMOnaV. OGuéganCChenMJackson-lewisVAndrewsL. JOlszewskiA. JStiegP. ELeeJ. PPrzedborskiSFriedlanderR. M2000Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science.288335339
  100. 100. LigonL. ALaMonte BH, Wallace KE, Weber N, Kalb RG, Holzbaur EL. 2005Mutant superoxide dismutase disrupts cytoplasmic dynein in motor neurons. Neuroreport.; 16533536
  101. 101. Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD. 1998. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 1998; 20:589.
  102. 102. LinHSchlaepferW. W2006Role of neurofilament aggregation in motor neuron disease. Ann Neurol; 60:399.
  103. 103. LingS. CAlbuquerqueC. PHanJ. SLagier-tourenneCTokunagaSZhouHClevelandD. W2010ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A 107:13318.
  104. 104. Liu-yesucevitzLet al2010Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLos ONE 5, e13250.
  105. 105. LocksleyR. MKilleenNLenardoM. J2001The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell; 104487501
  106. 106. MackenzieI. RRademakersRNeumannM2010TDP43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 99951007
  107. 107. MackenzieI. RBigioE. HInceP. GGeserFNeumannMCairnsN. JKwongL. KFormanM. SRavitsJStewartHEisenAMccluskyLKretzschmarH. AMonoranuC. MHighleyJ. RKirbyJSiddiqueTShawP. JLeeV. MTrojanowskiJ. Q2007Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. 615427434
  108. 108. MackenzieI. RBigioE. HInceP. GGeserFNeumannMCairnsN. JKwongL. KFormanM. SRavitsJStewartHEisenAMccluskyLKretzschmarH. AMonoranuC. MHighleyJ. RKirbyJSiddiqueTShawP. JLeeV. MTrojanowskiJ. Q2007Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 61542734
  109. 109. MagraneJManfrediG2009Mitochondrial function, morphology, and axonal transport in amyotrophic lateral sclerosis. Antioxidants & Redox Signaling; 11716151626
  110. 110. ManfrediGXuZ2005Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion; 57787
  111. 111. MantovaniSGarbelliSPasiniAAlimontiDPerottiCMelazziniMBendottiCMoraG2009Immune system alteration is sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J. Neuroimmunol. 210. 7379
  112. 112. MaragakisN. Jand Galvez-jimenezN2012Epidemiology and pathogenesis of amyotrophic lateral sclerosis. UpToDate; 116
  113. 113. Marchetto MCNMuotri A, Mu Y, Smith AM, Gage FH. 2008Non-Cell-Autonomous effect on human SODG37r astrocytes on motor neurons derived from human embryonic stem cells. Stem Cell; 3649657
  114. 114. MartinL. JGertzBPanYPriceA. CMolkentinJ. DChangQ2009The mitochondrial permeability transition pore in motor neuron involvement in the pathobiology of ALS mice. Experimental Neurology; (218)2:333-346
  115. 115. MartinL. J1999Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. 2000. J Neuropathol Exp Neurol ; 58:459.
  116. 116. MartinL. J1999Neuronal death in amyotrophic lateral sclerosis is apoptosis: possiblecontribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 58459471
  117. 117. MartinvaletDZhuPLiebermanJ2005Granzyme A induces caspase- independent mitochondrial damage, a required first step for apoptosis. Immunity; 2235570
  118. 118. MatsumotoSGotoSKusakaHImaiTMurakamiNHashizumeYOkazakiHHiranoA1993Ubiquitin-positive inclusion in anterior horn cells in subgroups of motor neuron diseases: a comparative study of adult-onset amyotrophic lateral sclerosis, juvenile amyotrophic lateral sclerosis and Werdnig-Hoffmann disease. J Neurol Sci;115220813
  119. 119. MattiazziMDAurelioMGajewskiC. DMartushovaKKialiMBealM. FManfrediG. 2002Mutated human SOD1 caused dysfunction of oxidative phosphorilation in mitochondrial of transgenic mice. The Journal of Biological Chemistry; (277)33:29626-29633
  120. 120. MenziesF. MCooksonM. RTaylorR. WTurnbullD. MChrzanowska-lightowlersZ. MDongLFiglewiczD. AShawP. J2002Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain; 12515221533
  121. 121. MilliganC. EOppenheimR. Wand SchwartzL. M1994Motoneurons deprived of trophic support in vitro require new gene expression to undergo programmed cell death. J Neurobiol 2510051016
  122. 122. MoisseKand M. JStrong2006Innate immunity in amyotrophic lateral sclerosis Biochim. Biophys. Acta; 176210831093
  123. 123. MorrisonB. MMorrisonJ. HGordonJ. WSuperoxide dismutase and neurofilament transgenic models of amyotrophic lateral sclerosis. J Exp Zool 1998
  124. 124. NagaiMReD. BNagataTChalazonitisAJessellT. MWichterleHPrzedborskiS2007Astrocytes expressing ALS-Linked mutated ALS release factors selectively toxic to motor neurons. Nat. Neurosci. 10615622
  125. 125. NangakuMSato-yoshitakeROkadaYNodaYTakemuraRYamazakiHHirokawaN1994KifBa novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Cell; 7912091220
  126. 126. NeumannMKwongL. KSampathuD. MTrojanowskiJ. QLeeV. M2007TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis. Arch Neurol. 6410138894
  127. 127. NeumannMSampathuD. MKwongL. KTruaxA. CMicsenyiM. CChouT. TBruceJSchuckTGrossmanMClarkC. MMccluskeyL. FMillerB. LMasliahEMackenzieI. RFeldmanHFeidenWKretzschmarH. ATrojanowskiJ. QLeeV. M2006Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science; 3145796130133
  128. 128. NichollsD. GVesceSKirkLChalmersS2003Interaction between mitochondrial bioenergetics and cytoplasma calcium in cultured cerebellar granule cells. Cell Calcium; (34)4-5:407-424.
  129. 129. NiwaJIshigakiSHishikawaNYamamotoMDoyuMMurataSTanakaKTaniguchiNSobueG2002Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. J Biol Chem.; 27739367938
  130. 130. OppenheimR. W1997Related mechanisms of action of growth factors and antioxidants in apoptosis: an overview. Adv Neurol 726978
  131. 131. Okado-matsumotoAFridovichI2001Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J Biol Chem.; 2763838838393
  132. 132. OkamotoKHiraiSAmariMWatanabeMSakuraiA1993Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett; 1962125128
  133. 133. Okamoto Y, Ihara M, Urushitani M, Yamashita H, Kondo T, Tanigaki A, Oono M, Kawamata J, Ikemoto A, Kawamoto Y, Takahashi R, Ito H. 2011. An autopsy case of SOD1-related ALS with TDP-43 positive inclusions. Neurology 2011; 77:1993.
  134. 134. PapadeasS. TS. EKraigC. OBanionA. CLeporeand N. JNagarkis2011Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo. Proc Natl Acad Sci U S A; (108)43:1703-17808.
  135. 135. PapadimitriouDVLeVercheAJacquier et al. 2010Inflammatory in ALS and SMA: sorting out the good from the evil. Neurobiol. Dis.; 37493502
  136. 136. PasinelliPand BrownR. H2006Molecular Biology of amyothrophic lateral sclerosis: insights from genetics. Nature; 7710723
  137. 137. PasinelliPBelfordM. ELennonNBacskaiB. JHymanB. TTrottiDBrown, Jr. RH. 2004Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron; 431930
  138. 138. PasinelliPBorcheltD. RHouseweartM. KClevelandD. WBrown Jr. RH. 1998Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A; 951576315768
  139. 139. PasinelliPHouseweartM. KBrown Jr. RH, Cleveland DW. 2000Caspase-1 and-3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 971390113906
  140. 140. PeharMCassinaPVargasM. RCastellanosRVieraLBeckmanJ. SEstévezA. GBarbeitoL2004Astrocytic production of nerve growth factor in motor neuron disorder apoptosis: implications for amyotrophic lateral slcerosis. J. Neurochem. 89464473
  141. 141. PhaniSD. BReSPrzedborski2012The role of the immune system in ALS. Frontiers in Pharmacology; (3)150:1-6.
  142. 142. PhilipsTRobberechtW2011Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol; 10:253.
  143. 143. PiaoY. SWakabayashiKKakitaAYamadaMHayashiSMoritaTIkutaFOyanagiKTakahashiH2003Neuropathology with clinical correlation of sporadic amyotrophoic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol 121022
  144. 144. PioroE. PMajorsA. WMitsumotoHNelsonD. RNgT. C1999H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology. 531719
  145. 145. PulsIJonnakutyCLaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH Jr, Ludlow CL, Fischbeck KH. 2003Mutant dynactin in motor neuron disease. Nat Genet. 3344556
  146. 146. PulsIOhS. JSumnerC. JWallaceK. EFloeterM. KMannE. AKennedyW. RWendelschafer-crabbGVortmeyerAPowersRFinneganKHolzbaurE. LFischbeckK. HLudlowC. L2005Distal spinal and bulbar muscular atrophy caused by dynactin mutation. Ann Neurol. 57687694
  147. 147. RaimondiAMangoliniARizzardiniMTartariSMassariSBendottiCFrancoliniMBorgeseNCantoniLPietriniG2006Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALS-linked G93ASOD1. Eur J Neurosci.; 24387399
  148. 148. RaoulCA. GEstévezHNishimuneD. WClevelandODelapeyrièreC. EHendersonGHaaseand BPettmann2002Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations. Neuron 3510671083
  149. 149. ReinerAMedinaLFigueredo-cardenasGAnfinsonS1995Brainstem motoneuron pools that are selectively resistant in amyotrophic lateral sclerosis are preferentially enriched in parvalbumin: evidence from monkey brainstem for a calcium-mediated mechanism in sporadic ALS. Exp Neurol.; 131239250
  150. 150. ReyesN. AFisherJ. KAustgenKVandenBerg S, Huang EJ, Oakes SA. 2010Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis. J Clin Invest 120:3673.
  151. 151. RobberechtWand PhilipsT2013The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14248264
  152. 152. RothsteinJ. D2009Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol 65 Suppl 1, S39
  153. 153. Rothstein JD Dunlop JBeal McIlvain H, She Y, Howland DS. 2003Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. J Neurosci; 23:1688.
  154. 154. RothsteinJ. DDykes-hobergMPardoC. A1996Knockout of glutamate transporters reveals a major role of astroglial transport in excitotoxicity and clearance of glutamate. Neuron; 16675686
  155. 155. RothsteinJ. DMartinL. JKunclR. W1992Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med; 32614641468
  156. 156. RothsteinJ. DTsaiGKunclR. WClawsonLCornblathD. RDrachmanD. BPestronkAStauchB. LCoyleJ. T1990Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol. 2811825
  157. 157. RothsteinJ. DVan KammenMLeveyA. IMartinL. JKunclR. W1995Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 387384
  158. 158. RothsteinJ. DVan KammenMLeveyA. I1995Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol; 387384
  159. 159. RowlandK. CIrbyN. KSpirouG. A2000Specialized synapse-associated structures within the calyx of Held. J Neurosci.; 2091359144
  160. 160. RutherfordN. JZhangY. JBakerMGassJ. MFinchN. AXuY. FStewartHKelleyB. JKuntzKCrookR. JSreedharanJVanceCSorensonELippaCBigioE. HGeschwindD. HKnopmanD. SMitsumotoHPetersenR. CCashmanN. RHuttonMShawC. EBoylanK. BBoeveBGraff-radfordN. RWszolekZ. KCaselliR. JDicksonD. WMackenzieI. RPetrucelliLRademakersR2008Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PloS Genet. 4(9):e1000193
  161. 161. SaelensXNFestjensLVandeWalleMVan GurpGvan Loo, P. Vandenabeele. 2004Toxic proteins released from mitochondria in cell death. Oncogene; 23286174
  162. 162. SasakiSIwataM1996Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. Neurology.; 47535540
  163. 163. SasakiSIwataM1996Ultrastructural study of synapses in the anterior horn neurons of patients with amyotrophic lateral sclerosis. Neurosci Lett.; 2045356
  164. 164. SasakiSMaruyamaS1994Immunocytochemical and ultrastructural studies of the motor cortex in amyotrophic lateral sclerosis. Acta Neuropathol; 87657885
  165. 165. SchulerMGreenD. R2001Mechanisms of 53apoptosis. Biochem Soc Trans. 29:684-8.
  166. 166. SchwabCAraiTHasegawaMAkiyamaHYuSMcgeerP. L2009TDP-43 pathology in familial British dementia. Acta Neuropatol.; 118230311
  167. 167. Shaw PJ, Forrest V, Ince PG, Richardson JP, Wastell HJ. 1995. CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration 1995; 4:209.
  168. 168. ShepherdG. MHarrisK. M1998Three-dimensional structure and composition of CA3-->CA1 axons in rat hippocampal slices: implications for presynaptic connectivity and compartmentalization. J Neurosci.; 1883008310
  169. 169. ShibataNHiranoAKobayashiMSiddiqueTDengH. XHungW. YKatoTAsayamaK1996Intense superoxide dismutase-1 immunoreactivity in intracytoplasmatic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol 55481490
  170. 170. ShookS. Jand PioroE. P2009Racing against the clock: recognizing, differenciating, diagnosisng, and referring the amyotrophic lateral sclerosis patient. Ann Neurol; 651016
  171. 171. SilaniVBragaMCiammolaVCardin, Scarlato G. 2000Motor neuron in culture as model to study ALS. Journal of Neurology ; (247)1:128-136.
  172. 172. SitteHWanschitzJBergerM2001Autoradiography with [3H] PK11195 of spinal tract degeneration in amyotrophic lateral sclerosis. Acta Neuropathologica; 1017578
  173. 173. Sotelo-silveiraJ. RLepantoPElizondoM. VHorjalesSPalaciosFMartinez Palma L, Marin M, Beckman JS, Barbeito L. 2009Axonal mitochondrial clusters containing mutant SOD1 in transgenic models of ALS. Antioxid Redox Signal.
  174. 174. SpoorenW. PBHengererDNA laddering and caspase 3like activity in the spinal cord of a mouse model of familial amyotrophic lateral sclerosis. Cell Mol Biol (Noisy-le-grand) 46:63.
  175. 175. Spreux-veroquauxOBensomonGLacomblezl2002Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis :reappraisal using a new HPLC method with coulometric detection in large cohort of patients. J Neurol Sci; 1937378
  176. 176. SreedharanJBlairI. PTripathiV. BHuXVanceCRogeljBAckerleySDurnallJ. CWilliamsK. LBurattiEBaralleFDe BellerocheJMitchellJ. DLeighP. NAl-chalabiAMillerC. CNicholsonGShawC. E2008TDP-43 mutation in familial and sporadic amyotrophic lateral sclerosis. Science. 319587016681672
  177. 177. StaMR. MSylva-steelandMCasulaet al2011Innate and adaptive immunity in amyotrophic lateral sclerosis : evidence of complement activation. Neurobiol. Dis.; 42211220
  178. 178. SterneckEKaplanD. RJohnsonP. F1996Interleukin-6 induces expression of peripherin and cooperates with Trk receptor signaling to promote neuronal differentiation in PC12 cells. J Neurochem.; 67:1365.
  179. 179. SturtzL. ADiekertKJensenL. TLillRCulottaV. C2001A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. J Biol Chem.; 2763808438089
  180. 180. SumiHKatoSMochimaruYFujimuraHEtohMSakodaS2009Nuclear TAR DNA binding protein 43 expression in spinal cord neurons correlates with the clinical course in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2009; 68:37.
  181. 181. TanC. FEguchiHTagawaAOnoderaOIwasakiTTsujinoANishizawaMKakitaATakahashiH2007TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with and without SOD1 gene mutation. Acta Neuropathol. 113, (5): 535-542.
  182. 182. TanC. FEguchiHTagawaAOnoderaOIwasakiTTsujinoANishizawaMKakitaATakahashiH2007TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. 113535542
  183. 183. TanakaYKanaiYOkadaYNonakaSTakedaSHaradaAHirokawaN1998Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell; 9311471158
  184. 184. TollerveyJ. RCurkTRogeljBBrieseMCeredaMKayikciMKönigJHortobágyiTNishimuraA. LZupunskiVPataniRChandranSRotGZupanBShawC. EUleJ2011Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14452458
  185. 185. TroostDSillevis Smitt PA, de Jong JM, Swaab DF. 1992Neurofilament and glial alterations in the cerebral cortex in amyotrophic lateral sclerosis. Acta Neuropathol; 84666473
  186. 186. TrottiDRolfsADanboltN. C1999SOD1 mutant linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci.; 2427433
  187. 187. Van DeerlinV. MLeverenzJ. BBekrisL. MBirdT. DYuanWElmanL. BClayDWoodE. MChen-plotkinA. SMartinez-lageMSteinbartEMccluskeyLGrossmanMNeumannMWuI. LYangW. SKalbRGalaskoD. RMontineT. JTrojanowskiJ. QLeeV. MSchellenbergG. DYuC. E2008TARDBP mutations in amyotrophic lateral sclerosis.with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 75409416
  188. 188. Van Den Bosch LVandenbergerghe W, Klaassen H, Van Houtte E, Robberecht W. 2000Ca (+2) permeable AMPA receptors and selective vulnerability of motor neurons. J Neurol Sci,; 1802934
  189. 189. Van Loo G, X. Saelens, M. van Gurp, M. MacFarlane, S.J. Martin, P. Vandenabeele. 2002. The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ.; 9:1031-42.
  190. 190. VanceCRogeljBHortobágyiTDe VosK. JNishimuraA. LSreedharanJHuXSmithBRuddyDWrightPGanesalingamJWilliamsK. LTripathiVAl-sarajSAl-chalabiALeighP. NBlairI. PNicholsonGDe BellerocheJGalloJ. MMillerC. CShawC. E2009Mutations in FUS, a RNA processing protein cause familial amyotrophic lateral sclerosis type 6. Science. 3235918120812011
  191. 191. Vande Velde CMiller TM, Cashman NR, Cleveland DW. 2008Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A.; 10540224027
  192. 192. VaradiAJohnson-cadwellL. ICirulliVYoonYAllanV. JRutterG. A2004Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1. J Cell Sci.; 11743894400
  193. 193. VijayvergiyaCBealM. FBuckJManfrediG2005Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. J Neurosci.; 2524632470
  194. 194. VukosavicSMDubois-dauphinM, NRomeroSPrzedborski1999Bax and Bcl-2 interaction in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem.; 7324602468
  195. 195. WajantH2002The Fas signaling pathway: more than a paradigm. Science; 29616356
  196. 196. WangLKSharmaK, GGrisottiRoosR. P2009The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol. Dis. 35234240
  197. 197. WilliamsT. LDayN. CInceP. GKambojR. KDhawP. J1997Calcium permeable alpha-3hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Ann Neurol; 43200207
  198. 198. WilliamsonT. LClevelandD. W1999Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci.; 25056
  199. 199. WintonM. JIgazL. MWongM. MKwongL. KTrojanowskiJ. QLeeV. M2008Disturbance of nuclear and cytoplasmatic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregrate formation. J. Biol. Chem. 2831330213309
  200. 200. WongN. KHeB. PStrongM. J2000Characterization of neuronal intermediate filament protein expression in cervical spinal motor neurons in sporadic amyotrophic lateral sclerosis (ALS). J Neuropathol Exp Neurol; 59:972.
  201. 201. WongP. CPardoC. ABorcheltD. RLeeM. KCopelandN. GJenkinsN. ASisodiaS. SClevelandD. WPriceD. L1995An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron.; 1411051116
  202. 202. XuY. FGendronT. FZhangY. JLinW. LDAltonSShengHCaseyM. CTongJKnightJYuXRademakersRBoylanKHuttonMMcgowanEDicksonD. WLewisJPetrucelliL. 2010Wild type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J. Neurosci. 301085110859
  203. 203. YaginumaHSatoNHommaSand OppenheimR. W2001Roles of caspases in the programmed cell death of motoneurons in vivo. Arch Histol Cytol 64461474
  204. 204. YokosekiAShigaATanC. FTagawaAKanekoHKoyamaAEguchiHTsujinoAIkeuchiTKakitaAOkamotoKNishizawaMTakahashiHOnoderaO2008TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 63453842
  205. 205. ZhangBTuPAbtahianFTrojanowskiJ. QLeeV. M1997Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol.; 13913071315
  206. 206. ZhangYOkoRVan Der HoornF. A2004Rat kinesin light chain 3 associates with spermatid mitochondria. Dev Biol.; 2752333
  207. 207. ZhuSI. GStavrovskayaMDrozdaB. YKimVOnaMLiSSarangA. SLiuD. MHartleyD. CWuSGullansR. JFerranteSPrzedborskiB. SKristalFriedlanderR. M2002Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateralsclerosis in mice. Nature; 4177478

Written By

Fabian H. Rossi, Maria Clara Franco and Alvaro G. Estevez

Submitted: 09 May 2012 Published: 11 September 2013

© 2013 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 2 Multiple Routes of Motor Neuron Degeneration in AL...

By Jin Hee Shin and Jae Keun Lee

3335 downloads

Chapter 3 Genetics of ALS and Correlations Between Genotype ...

By L. Diamanti, S. Gagliardi, C. Cereda and M. Ceroni

2325 downloads

Chapter 4 The Neuroinflammation in the Physiopathology of Am...

By Melissa Bowerman, Thierry Vincent, Frédérique Scam...

2692 downloads

Your cart

Discounts available on purchase of multiple copies. View rates

Subtotal £0.00

Local taxes (VAT) are calculated in later steps, if applicable.

Support: orders@intechopen.com