1. Introduction
In the last few years, it has become evident that the immunological component is of central importance in Parkinson’s Disease (PD) pathogenesis and progression. This can also certainly be said about the prominent role that the protein α-synuclein (αSyn) is currently believed to play in the pathobiology of this neurodegenerative disorder. Moreover, the multiple mechanisms through which αSyn might be affecting the immune system appear not to be just a consequence of disease progression, but to actively contribute to the delicate balance between neuroprotection and neurotoxicity that ultimately underlies a given stage of disease.
PD is a proteinopathy, whose pathological hallmark is the presence of deposits of aggregated αSyn in intracellular fibrillar inclusions in neurons of the
αSyn, together with β- and γ-synucleins, belong to the family of synucleins, a group of closely related, brain-enriched proteins. This 140 aa-residue protein is largely located in neuronal presynaptic terminals (Kim et al., 2004b) and in the nucleus (Yu et al., 2007). In particular, it is found in the neocortex, hippocampus and SN (Kim et al., 2004b), and in other brain regions, as well as within astrocytes, microglia and oligodendroglia (Austin et al., 2006; Mori et al., 2002; Richter-Landsberg et al., 2000). It is known to interact with a variety of proteins (Jenco et al., 1998; Peng et al., 2005) and lipid membranes (Jo et al., 2000). The physiological functions of αSyn are still being established, but its interaction with pre-synaptic membranes and lipids suggests a role in the regulation of synaptic vesicle pools including dopamine release control (Perez & Hastings, 2004) and in lipid metabolism (Cabin et al., 2002; Castagnet et al., 2005; Golovko et al., 2009).
Both
While αSyn is typically considered as an intracellular protein, it has also been found to be normally present in extracellular biological fluids, including human cerebrospinal fluid (CSF) and blood plasma (Borghi et al., 2000; El-Agnaf et al., 2003; El-Agnaf et al., 2006; Lee et al., 2006; Tokuda et al., 2006). However, αSyn levels have been found to be elevated in plasma from PD and multiple system atrophy (MSA) patients relative to age-matched controls (Lee et al., 2006), while lower levels than normal have been detected in CSF from PD patients (Tokuda et al., 2006). On the other hand, two studies by El-Agnaf and colleagues showed an elevated content of oligomeric αSyn spedies present in plasma (El-Agnaf et al., 2006) and post mortem CSF (Tokuda et al., 2010) from PD patients, compared to controls, indicating that changes in the levels and characteristics of extracellular αSyn are associated with the disease (Lee, 2008). Even though membrane permeability from dying cells could be one contributing factor, it has been suggested that vesicle-mediated exocytosis from normal cells is probably the main source of extracellular αSyn (Lee, 2008). By using brain homogenates and neuronal cell cultures, Lee and colleagues (Lee et al., 2005) have shown that both monomeric and aggregated αSyn can be secreted by an unconventional secretory pathway. On the other hand, extracellular αSyn has been shown to be taken up by neuronal and microglial cells in culture, although the nature of the mechanism involved is still controversial (Lee, 2008). In addition, two recent studies have provided strong evidence for a neuron-to-neuron and neuron-to-non-neuronal cell transmission of αSyn aggregates and their associated cytotoxicity, in cellular and mouse models of PD (Danzer et al., 2011; Desplats et al., 2009), highlighting the importance of extracellular αSyn in the pathogenic mechanism of α-synucleinopathies.
2. Neuroinflammation in PD
Another prominent pathological feature of PD brains is the presence of a robust inflammatory response mediated by activated microglia and reactive astrocytes in affected areas of the SN (Glass et al., 2010). Inflammation is the first response of the immune system to pathogens or irritation. In acute conditions, it protects tissue against invading agents and promotes healing. However, a chronic inflammatory state can turn harmful towards the host´s own tissue (Gao & Hong, 2008; Kim & Joh, 2006). Microglia are the resident immunocompetent cells in the brain (Aloisi, 2001), capable of antigen presentation to lymphocytes (Kreutzberg, 1996) and rapid activation in response to immune insults and invading of PD pathogenesis in the central nervous system (CNS) (Kim & Joh, 2006). As a result of pathogen invasion or tissue damage, microglia switch to an activated phenotype and thereby promote an inflammatory response that serves to further engage the immune system by recruiting other cells to the site of brain lesion, and initiate tissue repair (Glass et al., 2010). However, uncontrolled inflammation may result in production of neurotoxic factors that can be highly detrimental (Gao & Hong, 2008; Glass et al., 2010). Indeed, inflammation in the CNS and sustained overactivation of microglia, i.e. reactive microgliosis, are currently believed to be actively involved in the pathogenesis of various neurodegenerative diseases including PD, AD, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) (Gao & Hong, 2008; Glass et al., 2010; Kim & Joh, 2006; Long-Smith et al., 2009).
At present, whether microglial activation ultimately protects or actually exacerbates neuronal loss in the context of PD and other related diseases is still under debate (Delgado & Ganea, 2003; Gao & Hong, 2008; Halliday & Stevens, 2011; Sanchez-Pernaute et al., 2004; Vila et al., 2001; Wu et al., 2002; Wyss-Coray & Mucke, 2002), although the current view favours the second hypothesis. Evidence of microglial attack in PD is supported by findings from epidemiological studies, animal models, and cell culture experiments (McGeer & McGeer, 2008). Epidemiological studies have revealed that taking ibuprofen anti-inflammatory agent regularly is associated with a 35% lower risk of PD (Chen et al., 2005; Chen et al., 2003), supporting the concept that inflammatory attack is contributing to dopaminergic neuronal loss. On the other hand,
3. αSyn-induced microglial activation
The results gathered thus far using the different PD animal models have substantially increased our understanding of PD’s pathogenesis by usually providing different but probably complementary information. Thus, while the MPTP mouse model of PD indicates that inflammation in the SN can be self-propagating and leads to progressive neurodegeneration, the αSyn transgenic animal model demonstrates that overexpression of this endogenous protein can certainly provide a powerful source of inflammation (McGeer & McGeer, 2008). Whether microglial activation is essentially caused by the release of aberrant αSyn species to the extracellular space, (Reynolds et al., 2008b; Wersinger & Sidhu, 2006; Zhang et al., 2005), or otherwise, that neuronal death itself drives microglial immune responses in an αSyn-independent manner (Giasson et al., 2000; Mandel et al., 2005; Przedborski et al., 2001), is still under debate. However, there is ample accumulated evidence pointing at αSyn as the main trigger of microglial activation in PD (Roodveldt et al., 2008). For example, several studies have demonstrated that extracellular and nigral αSyn- containing aggregates are often surrounded by activated microglia or inflammatory mediators in PD brains (McGeer et al., 1988; Yamada et al., 1992), similarly to what has been described for amyloid plaques in AD (Griffin et al., 2006). Moreover, the extent of microglial activation in the SN from PD patients has been found to be correlated with the degree of αSyn accumulation (Croisier et al., 2005) and with increased αSyn levels as evidenced by in vitro (Kim et al., 2009; Klegeris et al., 2008) and in vivo (Lee et al., 2009a) studies, strongly supporting the view that the protein has a major role in phenotypic changes of microglia. Up to this point, a considerable number of
Two recent studies have explored the link between neuroinflammation and αSyn dysfunction by lipopolysacharide (LPS) injection in rat (Choi et al., 2010) or mice (Gao et al., 2011), to trigger systemic and brain inflammation. In the first study, the authors observed increased microglia activation and secretion of proinflammatory cytokines as well as greater nitration of proteins including αSyn, in elderly rats, suggesting that an exaggerated neuroinflammatory response that occurs naturally with aging might contribute to αSyn aggregation and dopaminergic neurodegeneration in PD (Choi et al., 2010). In the second study, the authors evaluated dopaminergic neurodegeneration, αSyn pathology and neuroinflammation in Wt and transgenic A53T αSyn-overexpressing mice (Gao et al., 2011). They observed that, while both models initially displayed acute neuroinflammation, only the latter developed persistent neuroinflammation together with chronic progressive degeneration of nigrostriatal dopamine pathway, accumulation of aggregated, nitrated αSyn, and formation of LB (Gao et al., 2011), suggesting that genetic factors and environmental exposures act synergistically to precipitate the development of PD. On the other hand, microglial cells from αSyn-knockout mice have been shown to exhibit a remarkably different morphology compared to Wt cells (Austin et al., 2006), displaying elevated levels of secreted pro-inflammatory cytokines such as TNF-α and IL-6 after activation, indicating that αSyn plays a critical role in modulating the microglial activation state. More recently, the authors have found that microglial activation in this model is accompanied by increased protein levels of three enzymes involved in lipid-mediated signalling, which suggests a broader function for αSyn in brain physiology beyond synapsis control (Austin et al., 2011).
In the last few years, several
Up to this point, research on αSyn-mediated cell response has focused primarily on the effects on neuroinflammation (Benner et al., 2008) or microglial activation (Cookson, 2009; Reynolds et al., 2008a; Thomas et al., 2007; Zhang et al., 2007; Zhang et al., 2005) of αSyn in its aggregated form. Interestingly, Reynolds and coworkers (Reynolds et al., 2008b) have found that nitrated, aggregated αSyn (N-αSyn) has a stronger stimulating effect on microglia than that of nitrated but non-aggregated αSyn. In addition, several investigations have found that N-αSyn, which has been detected in LB of human brains with PD (Giasson et al., 2000) and has been linked to neurodegeneration in PD mouse models (Benner et al., 2008; Gao et al., 2008), induces a neurotoxic inflammatory microglial phenotype that accelerates dopaminergic neuronal loss (Biasini et al., 2004; Thomas et al., 2007; Zhang et al., 2005; Zhou et al., 2005). By integrating genomic and proteomic techniques, Gendelman and colleagues created a fingerprint of microglial cell activation following its interactions with aggregated N-αSyn in cell culture (Reynolds et al., 2008a), indicating that the activation, which was found to be capable of mediating dopaminergic neurotoxicity, is mainly mediated by the NF-κB pathway (Reynolds et al., 2008a). However, whether extracellular αSyn contains the same modifications than the protein found in LB (Anderson et al., 2006; Giasson et al., 2000; Hodara et al., 2004), which is a typically pro-oxidative environment, is still uncertain (Lee, 2008).
Over the last few years, certain differential functions for non-aggregated, extracellular aSyn in glia have been reported. It has been observed that, in contrast to the aggregated form, monomeric αSyn enhances microglial phagocytosis (Park et al., 2008). A few investigations that explore the effects of non-aggregated αSyn on the cytokine release profile of potentially relevant cells have been recently done using monocytic (Klegeris et al., 2008) or macrophage (Lee et al., 2009b) cell lines, and primary astrocyte (Klegeris et al., 2006) or microglial (Roodveldt et al., 2010; Su et al., 2009; Su et al., 2008) cultures. Indeed, we have observed a strong innate immune response in primary glial and microglial cell cultures elicited by exogenous, non-aggregated αSyn (Roodveldt et al., 2010). Interestingly, a comparative study using unmodified aSyn has recently shown that exogenous non-aggregated αSyn induces higher TNF-α, IL-1β and ROS release levels than aggregated αSyn in microglia (Lee et al., 2010). These and other recent findings point at the importance of exploring the effects on the immune response of aggregated as well as non-aggregated αSyn.
Even though a study using monocytic THP-1 cell line (Klegeris et al., 2008) had shown modest increases in IL-1β and TNF-α secretion levels after stimulation with A30P, A53T, or E46K αSyn mutants compared to the Wt protein, there is a lack of a comprehensive study of the effect exerted by non-aggregated αSyn, performed with primary cell cultures. With this in mind, we analysed the cytokine release profile of primary microglial cultures ―which represesnts a more comparable physiological environment― after stimulation with Wt or the PD-linked αSyn mutants (Roodveldt et al., 2010). Indeed, we found remarkable differences between the αSyn variants in the interleukin and chemokine release profiles and significant effects on the microglial phagocytic capacity (Roodveldt et al., 2010). In particular, we observed marked differences in IL-6 and IL-1β pro-inflammtory cytokines, IL-10 immunoregulatory cytokine, as well as IP-10/CXCL10, RANTES/CCL5, MCP-1/CCL2 and MIP-1α/CCL3 chemokines release levels. Our results indicate that extracellular, non-aggregated Wt αSyn produces a moderate to low pro-inflammatory response in glia, together with a reduction of the immunoregulatory response, and a moderate stimulation of Th1 chemokine secretion. The A30P and E46K pathological variants, on the other hand, can induce strong pro-inflammatory and immunoregulatory responses, together with marked increases in chemokine release levels. This exacerbated innate immune response might explain the earlier onset and more rapid evolution of these two genetic cases of PD as compared to the sporadic kind. Intriguingly, our results from the pathologically-linked A53T variant showed not to provoke a significant innate immune response, which might suggest that other neurodegeneration mechanisms contributing to the pathogenesis of PD, probably involving the adaptive immune response, might exist in this case. Combined with the effect on microglial phagocytosis, our results indicate that these αSyn-induced phenotypes might reflect either a classical (A30P and E36K) or an alternative (A53T) microglial activation state, or a hybrid phenotype (Wt), which could probably explain the different disease progression modes that can occur in PD. Alternative activation of macrophages and microglia is a response to tissue injury that is thought to be involved in tissue repair and restoration (Ponomarev et al., 2007), and has been suggested to play a role in repair and extracellular matrix remodelling in AD (Colton et al., 2006). Currently, there is no other indication that such an activation mode could be operating in the context of PD.
Upon activation, microglia and astrocytes start secreting inflammatory cytokines in order to communicate and mount the immune response to counteract disease or injury. The cytokines TNF-α, IL-1β, IL-2, IL-4, IL-6, TGF-α, TGF-β1, TGF-β2 have all been reported to be increased in the nigrostriatal region and CSF of patients with PD or DLB (Croisier & Graeber, 2006). As a result of αSyn-induced activation of microglia
Activated microglia can also produce substantial amounts of superoxide radicals, which may be the major source of the oxidative stress thought to be largely responsible for dopaminergic cell death in PD. The generation of ROS by microglia activated by αSyn (Thomas et al., 2007) can result in oxidation and nitration of proteins, DNA modifications, and lipid peroxidation, leading to neurotoxicity (Zhang et al., 2005). Oxidation (Ko et al., 2000; Souza et al., 2000) and nitration (Giasson et al., 2000; Souza et al., 2000) of αSyn, in turn, can lead to the formation of more aggregates, which could result in increased cytotoxic effects. Consistent with this, Kelly
Further insight into the mechanism of pathogenesis might derive from the findings that several proteins which are thought to be linked to PD are up-regulated as a result of αSyn-induced microglial activation. Gendelman and co-workers, by determining the activated microglia proteome profile (Reynolds et al., 2008a), found that aggregated N-αSyn activation of microglia results in differential expression of several proteins. These range from proteins involved in oxidative stress, cell adhesion, glycolysis, growth control, and migration, to cytoskeletal proteins. It is worth noting that two of those proteins found to be most up-regulated, calmodulin and ubiquitin, have been shown to interact with αSyn with possible functional consequences. Calmodulin has been shown,
4. Links between αSyn and astrocytes and oligodendrocytes
Together with microglial cells, astrocytes and oligodendrocytes are part of glia, which normally serve neuroprotective functions but, given adverse stimulation as discussed before, they may contribute to develop chronic neuroinflammation (Halliday & Stevens, 2011; McGeer & McGeer, 2008). Compared to microglia, the functions of astrocytes are poorly understood. Because they have been shown to produce both pro-inflammatory and anti-inflammatory agents, these cells are thought to have a dual role (McGeer & McGeer, 2008). Many ICAM-1-positive astrocytes are seen in the SN of PD brains and this may attract reactive microglia to the area since microglia carry the counter receptor LFA-1 (Miklossy et al., 2006). Indeed, αSyn has been shown to be capable of both of activating microglia and stimulating astrocytes to produce IL-6 and ICAM-1 (Klegeris et al., 2006). On the other hand, astrocytes have been shown to secrete a number of neurotrophic factors that protect dopaminergic neurons in some models of PD (McGeer & McGeer, 2008), but the mechanisms underlying most of these functions are not yet known. Astrocytes have been shown to express αSyn (Tanji et al., 2001). Interestingly, the presence of αSyn-containing inclusion bodies in astrocytes of sporadic PD brains has been observed (Braak et al., 2007; Terada et al., 2003; Wakabayashi et al., 2000). Finally, a recent study showed that astrocyte expression of A53T αSyn leads to the development of progressed paralysis, strong microglial activation, and neurodegeneration (Gu et al., 2010).
There is still little data on the role of oligodendrocytes in PD. αSyn-containing inclusions have been detected in this cell type in MSA, in DLB, and in PD (Campbell et al., 2001; Wakabayashi et al., 2000). McGeer and colleagues have reported the presence of complement-activated oligodendrocytes in the SN of PD cases (Yamada et al., 1992). Intriguingly, transgenic mice overexpressing Wt αSyn in oligodendrocytes have been observed to develop severe neurological alterations and neurodegeneration (Shults et al., 2005; Yazawa et al., 2005), drawing the attention to a possible role of these glial cells in PD.
5. Expression of αSyn by immunocompetent cells
Given that αSyn expression has been reported also in non-neuronal cells, it is currently thought to play a role besides dopamine release control. While searching for a link between the CNS and peripheral immune system in PD, Kim
6. αSyn and the adaptive immune response in PD
In the last few years, mounting evidence has pointed at a possible participation of the adaptive immune system in PD pathogenesis. However, whether this immune response actually contributes to neurodegeneration, and in that case by which mechanism, remains unknown. The initial observations in PD patients that a small amount of CD8+ T-lymphocytes occur in proximity to degenerating nigral neurons (McGeer et al., 1988), and the occurrence in LB of components of the classical or antibody-triggered complement cascade (Yamada et al., 1992) had suggested a possible involvement of the adaptive immunity in the PD process. More recently, the finding of accumulated IgG in the SN of PD patients and increased expression of IgG-binding receptors on activated microglia (Orr et al., 2005), and the detection of anti-αSyn autoantibodies (AAb) in blood serum of PD patients (Papachroni et al., 2007), suggest that the pathological process may involve adaptive immune-mediated mechanisms. In addition, the observation that humoral immune mechanisms can trigger microglial-mediated neuronal injury in animal models of PD (He et al., 2002), and the finding by Standaert and colleagues of IgG deposition in mouse brains following AAV-mediated αSyn overexpression in the SN (Theodore et al., 2008), further support a role of the adaptive immune system in disease progression.
A possible consequence of the initial microglial activation in the affected regions of PD brains is the local permeabilization of the blood-brain barrier (BBB), leading to infiltration to the affected regions by B- and/or T-lymphocytes (Racke et al., 2000). Indeed, a remarkable T- and B-cell infiltration into the SN linked to αSyn overexpression was observed at the early stages, i.e. before the appearance of significant dopaminergic neuronal loss, reaching levels in the SN of up to 10-fold and 5-fold compared to controls (Theodore et al., 2008). A recent study by Hunot and colleagues (Brochard et al., 2009) has shown that CD8+ and CD4+ T-cells, but not B-cells, had invaded the brain in PD patients and in MPTP-treated mice during the course of neural degeneration. Furthermore, based on these results the authors propose that T-cell dependant toxicity is essentially mediated by CD4+ T-cells and requires the expression of FasL (Brochard et al., 2009). Given that the FasL pathway had been shown to produce proinflammatory cytokine responses in macrophages (Park et al., 2003), the authors speculate that the CD4+ Th FasL-mediated activation of microglia could participate in neuroinflammation and neurodegeneration processes in PD (Brochard et al., 2009).
Based on results obtained with an MPTP murine model of the disease, Gendelman and colleagues (Reynolds et al., 2010) have suggested that the αSyn-specific regulatory T-cells (Treg cells), which are regulatory components of the adaptive immunity, might be able to counteract the autoaggresive effector T-cell responses that exacerbate neuroinflammation (Benner et al., 2008), and therefore contribute to attenuate neurodegeneration in PD. Indeed, the same group has reported that microglial cells stimulated with N-αSyn are susceptible of essentially opposing immune regulatory responses by Treg cells (CD4+, CD245+) and effector T-cells (CD4+, CD25-) in culture (Reynolds et al., 2009a). By analysing an array of cytokines released by treated microglia, the authors found that, while the effector T-cell subset exacerbates microglial-mediated inflammation and may induce neurotoxic responses, Treg cells are able to suppress N-αSyn microglial-induced reactive-oxygen species (ROS) and NF-κB activation and are proposed to be neuroprotective (Reynolds et al., 2009a). Furthermore, the study indicates that Treg cells can regulate microglial inflammation by inducing Fas-FasL-mediated apoptosis of N-αSyn-stimulated microglial cells (Reynolds et al., 2009a). By using a proteomic analysis, the authors further showed that these Treg cells can significantly alter the microglial protein expression profile for certain proteins linked to cell metabolism, migration, protein transport and degradation, redox biology, and cytoskeletal and bioenergetic metabolism, to presumably attenuate the neurotoxic phenotype caused by N-αSyn stimulation (Reynolds et al., 2009b).
Thus far, accumulated data demonstrate that in the MPTP model of PD, misfolded and aggregated αSyn are secreted from neurons, which promotes pro-inflammatory M1-type microglia and cytotoxic T-cells, therefore amplifying neuronal damage. In sporadic human PD, it is currently unkown which factor triggers disease onset, but it has been proposed that under certain circumstances, a similar set of temporal and mechanistic events could transform neuroprotective microglia and T cells into cytotoxic cells, thereby accelerating disease progression (Appel et al., 2010). This way, activated microglia and the cytokine milieu that they generate might promote T-cell differentiation into different cell subsets in the context of PD (Appel et al., 2010). Indeed, it has been shown that M1 (pro-inflammatory) cells promote, whereas M2 (non-inflammatory) cells reduce, CD4+ Th1 cell proliferation and function (Verreck et al., 2004), but also that, conversely, T-cells can dictate microglial pro- or anti-inflammatory phenotypes (Giuliani et al., 2003; Kebir et al., 2007; Mount et al., 2007). Whether microglia dictate the specific T-cell phenotype or otherwise, that T-cells dictate the specific microglial phenotype (i.e. M1
To analyse the possibility that humoral immunity may play a role in initiating or regulating inflammation, Orr
The question regarding the functional importance of antibodies against antigen-specific, disease-associated neuronal proteins still needs to be addressed. It has been demonstrated that an IgG fraction purified from serum of PD patients causes death of dopaminergic neurons
A recent study has assessed the presence of auto-antibodies (AAb) against all three synucleins in the peripheral blood serum of PD patients and healthy controls (Papachroni et al., 2007). While the presence of AAb against β- and γ-Syn showed no association with PD, multi-epitopic AAb against αSyn were detected in 65% of all patients, with a strong correlation with the inherited mode of the disease. In addition, a recent study based on measuring AAb levels against monomeric, oligomeric, and fibrillar αSyn in serum from PD patients (Gruden et al., 2011), showed that all three AAb specificities reached the highest values after 5-year of disease duration, and subsided in 10-year sufferers. Intriguingly, there was a ca. 15-fold increase in AAb titre values relative to monomeric αSyn (72% of patients), and a ca. 4-fold increase for αSyn oligomers (56% of patients). Moreover, the authors also found a decline in CD3+, CD4+ and CD8+ T-lymphocyte and B-lymphocyte subsets. Based on these results, they suggest that αSyn toxicity elimination by AAb in early PD pathology might be linked with the decline of lymphocyte subsets reflecting the influence of inflammatory and oxidative stress processes (Gruden et al., 2011).
Despite their potential involvement in PD pathogenesis and progression, the role of NK cells in PD has hardly been explored. NK cells are active members of the innate immune system that act as a first-line defence, and also mediate between the innate and adaptive immune systems (Salazar-Mather et al., 1996; Su et al., 2001). Interestingly, a recent study using blood samples from PD patiens indicates that the NK activity increases as the disease advances (Mihara et al., 2008). Moreover, the study also showed that the NK cell content among the total lymphocytes of the PD group was higher than in the control group (Mihara et al., 2008).
7. Prospects for αSyn-based immunotherapy in PD
In addition to its well known importance in the pathogenesis of PD, αSyn is becoming a primary target for preventing or controlling the process of PD. In the late few years, vaccination for treating some neurodegenerative disorders has emerged as a potentially useful approach. Thus far, this avenue has been scarcely explored for PD. Importantly, immunization with αSyn was shown to generate a humoral response in a mouse model of PD (Masliah et al., 2005), producing beneficial albeit modest results on histopathological markers of the disease. On the contrary, using N-αSyn as the immunogen proved to elicit strong antigen-specific effector T cell responses in MPTP-intoxicated mice that caused exacerbated neuroinflammation and neurodegeneration (Benner et al., 2008). This response was further shown to be largely mediated by Th17 cells and causing Treg dysfunction (Reynolds et al., 2010). In addition, the authors demonstrated that Treg cells from mice treated with the neuropeptide VIP, known to promote Treg responses (Delgado et al., 2005; Gonzalez-Rey et al., 2006), can efficiently modulate N-αSyn-generated immunity in MPTP mice and confer neuroprotection (Reynolds et al., 2010), suggesting a possible novel therapeutic avenue for PD.
Given that microglial activation can maintain or even aggravate the disease process, blocking inflammation or shifting the balance between pro-inflammatory and anti-inflammatory states in a controlled manner, offers one of the most promising strategies for developing palliative (and maybe preventive) therapies for PD and related disorders. Epidemiological data have identified the non steroidal anti-inflammatory drug (NSAID) ibuprofen as neuroprotective for PD (Klegeris et al., 2007b). NSAIDs are thought to act on dopamine quinone formation and activation by αSyn of both astrocytes and microglia. On the other hand, Gendelman and colleagues demonstrated that T cells from mice immunized with Copolymer-1 (Cop-1), are able to attenuate microglial responses and lead to neuroprotection in a MPTP mouse model of PD (Benner et al., 2004). This neuroprotective effect was later found to be mediated by the CD4+ type of T cells, suggesting the possible involvement of Treg cells (Laurie et al., 2007). Later work by the same group confirmed this hypothesis by showing that passive transfer to MPTP mice of activated Treg cells, but not effector T cells, efficiently suppressed microglial activation and afforded neuroprotection (Reynolds et al., 2007), suggesting that the immunomodulating abilities of Treg cells could potentially be utilized as a therapeutic approach against PD (Stone et al., 2009).
8. Conclusion
It is well established that PD onset and progression are characterized by sustained activation of microglia, linked to significant dopaminergic neuron loss in the SN of the brain. Over the last few years, it has become accepted that overexpression and aggregation of αSyn, an amyloid-like protein, is linked to neurotoxicity through various proposed mechanisms, and may be one of the primary causes of the immunological abnormalities observed in PD. Recent studies with cellular and
Accumulated evidence has now established that aggregated extracellular αSyn is able to trigger the activation of microglia, inducing a highly detrimental cascade of neuroinflammation and neuronal demise. In addition, recent studies have have demonstrated that non-aggregated αSyn can also have a substantial impact on microglial phenotype and cytokine release profile, especially in the cases of familial PD αSyn mutants. By releasing toxic factors, or by phagocytosing neighbouring cells, activated microglia and astrocytes are believed to form a self-perpetuating neuronal degeneration cycle. On the other hand, recent findings point at a possible role of the adaptive immune system involving αSyn, and the pathological process in PD. Clearly, further studies in this direction are necessary to help understand the complex immunological mechanisms underlying PD and the key, and possibly multiple, links between αSyn and the immune response in relation to in relation to pathogenesis (Figure 1).
In addition to trying to develop effective tools to prevent αSyn aggregation, modulating the innate immune response by intervening microglial activation, promoting a selective aSyn-specific humoral response, and manipulating the balance between effector and immunomodulatory T-cell populations, may be considered as highly promising therapeutic approaches for the treatment of PD and other synucleinopathies.
Acknowledgments
We gratefully acknowledge the financial support provided by the Spanish Ministry of Science and Innovation-Carlos III Institute of Health according to the ‘Plan Nacional de I+D+I 2008-2011’ (PS09-2252 to DP, and CP10/00527 to CR, with cofunding by FEDER), the Andalusian Ministry of Health (PI-2010-0824 to DP), and the PAIDI Program from the Andalusian Government (CTS-677 to DP). ALG holds a FPU predoctoral fellowship from the Spanish Ministry of Education. We are most indebted to Neuroinvest Foundation for its continuing support.
References
- 1.
Aloisi F. 2001 Immune function of microglia. , 36, (2),165 179 ). - 2.
Alvarez-Erviti L. et al. 2011 Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line . , 69, (4),337 342 ). - 3.
Anderson J. P. et al. 2006 Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. , 281, (40),29739 29752 ). - 4.
Appel S. H. et al. 2010 T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? , 31, (1),7 17 ). - 5.
Auluck P. K. et al. 2002 Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. , 295, (5556),865 868 ). - 6.
Austin S. A. et al. 2006 Alpha-synuclein expression modulates microglial activation phenotype. , 26, (41),10558 10563 ). - 7.
Austin S. A. et al. 2011 Lack of Alpha-Synuclein modulates microglial phenotype In Vitro . , 36, (6),994 1004 ). - 8.
Baglioni S. et al. 2006 Prefibrillar amyloid aggregates could be generic toxins in higher organisms. , 26, (31),8160 8167 ). - 9.
Benner E. J. et al. 2008 Nitrated alpha-Synuclein immunity accelerates degeneration of nigral dopaminergic neurons. , 3, (1),e1376 . - 10.
Benner E. J. et al. 2004 Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease . , 101, (25),9435 9440 ). - 11.
Bennett M. C. 2005 The role of alpha-synuclein in neurodegenerative diseases. , 105, (3),311 331 ). - 12.
Biasini E. et al. 2004 Proteasome inhibition and aggregation in Parkinson’s disease: a comparative study in untransfected and transfected cells . , 88, (3),545 553 ). - 13.
Borghi R. et al. 2000 Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. , 287, (1),65 67 ). - 14.
Bosco D. A. et al. 2006 Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. , 2, (5),249 253 ). - 15.
Braak H. et al. 2003 Staging of brain pathology related to sporadic Parkinson’s disease. , 24, (2),197 211 ). - 16.
Braak H. et al. 2007 Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. , 114, (3),231 241 ). - 17.
Brochard V. et al. 2009 Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease . , 119, (1),182 192 ). - 18.
Bucciantini M. et al. 2004 Prefibrillar amyloid protein aggregates share common features of cytotoxicity. , 279, (30),31374 31382 ). - 19.
Bucciantini M. et al. 2002 Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. , 416, (6880),507 511 ). - 20.
Cabin D. E. et al. 2002 Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. , 22, (20),8797 8807 ). - 21.
Campbell B. C. et al. 2001 The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. , 76, (1),87 96 ). - 22.
Castagnet P. I. et al. 2005 Fatty acid incorporation is decreased in astrocytes cultured from alpha-synuclein gene-ablated mice. , 94, (3),839 849 ). - 23.
Castano A. et al. 1998 Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system . , 70, (4),1584 1592 ). - 24.
Colton C. A. et al. 2006 Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD . , 3,27 . - 25.
Cookson M. R. 2009 alpha-Synuclein and neuronal cell death. , 4,9 . - 26.
Croisier E. Graeber M. B. 2006 Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration . , 112, (5),517 530 ). - 27.
Croisier E. et al. 2005 Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. , 2,14 . - 28.
Chen H. et al. 2005 Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. , 58, (6),963 967 ). - 29.
Chen H. et al. 2003 Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. , 60, (8),1059 1064 ). - 30.
Chen S. et al. 1998 Experimental destruction of substantia nigra initiated by Parkinson disease immunoglobulins. , 55, (8),1075 1080 ). - 31.
Chiti F. Dobson C. M. 2006 Protein misfolding, functional amyloid, and human disease. , 75,333 366 ). - 32.
Choi D. Y. et al. 2010 Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats. , 31, (9),1649 1653 ). - 33.
Chung C. Y. et al. 2009 Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. , 29, (11),3365 3373 ). - 34.
Danzer K. M. et al. 2011 Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. , 25, (1),326 336 ). - 35.
Dedmon M. M. et al. 2005 Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. , 280, (15),14733 14740 ). - 36.
Delgado M. et al. 2005 Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. , 78, (6),1327 1338 ). - 37.
Delgado M. Ganea D. 2003 Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation. , 17, (8),944 946 ). - 38.
Desplats P. et al. 2009 Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. , 106, (31),13010 13015 ). - 39.
El -Agnaf O. M. et al. 2003 Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. , 17, (13),1945 1947 ). - 40.
El -Agnaf O. M. et al. 2006 Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. , 20, (3),419 425 ). - 41.
Fernagut P. O. Chesselet M. F. 2004 Alpha-synuclein and transgenic mouse models. , 17, (2),123 130 ). - 42.
Gao H. M. Hong J. S. 2008 Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. , 29, (8),357 365 ). - 43.
Gao H. M. et al. 2008 Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. , 28, (30),7687 7698 ). - 44.
Gao H. M. et al. 2011 Neuroinflammation and alpha-Synuclein dysfunction potentiate each other driving chronic progression of neurodegeneration in a mouse model of Parkinson’s disease. , pp. - 45.
Gasser T. 2005 Genetics of Parkinson’s disease. , 18, (4),363 369 ). - 46.
Giasson B. I. et al. 2000 Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. , 290, (5493),985 989 ). - 47.
Giorgi C. et al. 2008 Ca2+ signaling, mitochondria and cell death. , 8, (2),119 130 ). - 48.
Giuliani F. et al. 2003 Vulnerability of human neurons to T cell-mediated cytotoxicity. , 171, (1),368 379 ). - 49.
Glass C. K. et al. 2010 Mechanisms underlying inflammation in neurodegeneration. , 140, (6),918 934 ). - 50.
Golovko M. Y. et al. 2009 The role of alpha-synuclein in brain lipid metabolism: a downstream impact on brain inflammatory response. , 326, (1-2),55 66 ). - 51.
Gonzalez-Rey E. et al. 2006 Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. , 107, (9),3632 3638 ). - 52.
Griffin W. S. et al. 2006 Interleukin-1 mediates Alzheimer and Lewy body pathologies. , 3,5 . - 53.
Gruden M. A. et al. 2011 Immunoprotection against toxic biomarkers is retained during Parkinson’s disease progression. , pp. - 54.
Gu X. L. et al. 2010 Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. , 3,12 . - 55.
Halliday G. M. Stevens C. H. 2011 Glia: Initiators and progressors of pathology in Parkinson’s disease. , 26, (1),6 17 ). - 56.
Hasegawa M. et al. 2002 Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. , 277, (50),49071 49076 ). - 57.
He Y. et al. 2002 Role of Fcgamma receptors in nigral cell injury induced by Parkinson disease immunoglobulin injection into mouse substantia nigra. , 176, (2),322 327 ). - 58.
Hodara R. et al. 2004 Functional consequences of alpha-synuclein tyrosine nitration: diminished binding to lipid vesicles and increased fibril formation. , 279, (46),47746 47753 ). - 59.
Huang C. et al. 2006 Heat shock protein 70 inhibits alpha-synuclein fibril formation via interactions with diverse intermediates. , 364, (3),323 336 ). - 60.
Jenco J. M. et al. 1998 Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. , 37, (14),4901 4909 ). - 61.
Jo E. et al. 2000 alpha-Synuclein membrane interactions and lipid specificity. , 275, (44),34328 34334 ). - 62.
Kawai T. Akira S. 2007 TLR signaling. , 19, (1),24 32 ). - 63.
Kebir H. et al. 2007 Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. , 13, (10),1173 1175 ). - 64.
Kim S. et al. 2009 Alpha-synuclein induces migration of BV-2 microglial cells by up-regulation of CD44 and MT1-MMP. , 109, (5),1483 1496 ). - 65.
Kim S. et al. 2004a Alpha-synuclein induces apoptosis by altered expression in human peripheral lymphocyte in Parkinson’s disease. , 18, (13),1615 1617 ). - 66.
Kim S. et al. 2004b Alpha-synuclein, Parkinson’s disease, and Alzheimer’s disease. , 10 Suppl 1,S9 13 ). - 67.
Kim Y. S. Joh T. H. 2006 Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. , 38, (4),333 347 ). - 68.
Klegeris A. et al. 2007a Functional ryanodine receptors are expressed by human microglia and THP-1 cells: Their possible involvement in modulation of neurotoxicity. , 85, (10),2207 2215 ). - 69.
Klegeris A. et al. 2006 Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. , 20, (12),2000 2008 ). - 70.
Klegeris A. et al. 2007b Therapeutic approaches to inflammation in neurodegenerative disease. , 20, (3),351 357 ). - 71.
Klegeris A. et al. 2008 Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia. , 29, (5),739 752 ). - 72.
Klucken J. et al. 2004 Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity. , 279, (24),25497 25502 ). - 73.
Ko L. et al. 2000 Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein. , 75, (6),2546 2554 ). - 74.
Kreutzberg G. W. 1996 Microglia: a sensor for pathological events in the CNS. , 19, (8),312 318 ). - 75.
Kruger R. et al. 1998 Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. , 18, (2),106 108 ). - 76.
Laurie C. et al. 2007 CD4+ T cells from Copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. , 183, (1-2),60 68 ). - 77.
Lee D. et al. 2002 alpha-Synuclein exhibits competitive interaction between calmodulin and synthetic membranes. , 82, (5),1007 1017 ). - 78.
Lee E. J. et al. 2010 Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. , 185, (1),615 623 ). - 79.
Lee H. J. et al. 2005 Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. , 25, (25),6016 6024 ). - 80.
Lee J. K. et al. 2009a Neuroinflammation in Parkinson’s disease. , 4, (4),419 429 ). - 81.
Lee J. T. et al. 2008 Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. , 17, (6),906 917 ). - 82.
Lee P. H. et al. 2006 The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy. , 113, (10),1435 1439 ). - 83.
Lee S. B. et al. 2009b Identification of the amino acid sequence motif of alpha-synuclein responsible for macrophage activation. , 381, (1),39 43 ). - 84.
Lee S. J. 2008 Origins and effects of extracellular alpha-synuclein: implications in Parkinson’s disease. , 34, (1),17 22 ). - 85.
Lim K. L. Tan J. M. 2007 Role of the ubiquitin proteasome system in Parkinson’s disease. , 8 Suppl 1,S13 . - 86.
Long-Smith C. M. et al. 2009 The influence of microglia on the pathogenesis of Parkinson’s disease. , 89, (3),277 287 ). - 87.
Mandel S. et al. 2005 Gene expression profiling of sporadic Parkinson’s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. , 1053,356 375 ). - 88.
Martinez J. et al. 2003 Parkinson’s disease-associated alpha-synuclein is a calmodulin substrate. , 278, (19),17379 17387 ). - 89.
Masliah E. et al. 2005 Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. , 46, (6),857 868 ). - 90.
Mc Geer P. L. et al. 1988 Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. , 38, (8),1285 1291 ). - 91.
Mc Geer P. L. Mc Geer E. G. 2008 Glial reactions in Parkinson’s disease. , 23, (4),474 483 ). - 92.
Mihara T. et al. 2008 Natural killer cells of Parkinson’s disease patients are set up for activation: a possible role for innate immunity in the pathogenesis of this disease. , 14, (1),46 51 ). - 93.
Miklossy J. et al. 2006 Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. , 197, (2),275 283 ). - 94.
Mori F. et al. 2002 Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. , 176, (1),98 104 ). - 95.
Mount M. P. et al. 2007 Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. , 27, (12),3328 3337 ). - 96.
Orr C. F. et al. 2005 A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. , 128, (Pt 11),2665 2674 ). - 97.
Ouchi Y. et al. 2005 Microglial activation and dopamine terminal loss in early Parkinson’s disease. , 57, (2),168 175 ). - 98.
Papachroni K. K. et al. 2007 Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. , 101, (3),749 756 ). - 99.
Park D. R. et al. 2003 Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophages. , 170, (12),6209 6216 ). - 100.
Park J. Y. et al. 2008 Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. , 56, (11),1215 1223 ). - 101.
Peng X. et al. 2005 Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. , 118, (Pt 15),3523 3530 ). - 102.
Perez R. G. Hastings T. G. 2004 Could a loss of alpha-synuclein function put dopaminergic neurons at risk? , 89, (6),1318 1324 ). - 103.
Polymeropoulos M. H. et al. 1997 Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. , 276, (5321),2045 2047 ). - 104.
Ponomarev E. D. et al. 2007 CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. , 27, (40),10714 10721 ). - 105.
Przedborski S. et al. 2001 Oxidative post-translational modifications of alpha-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. , 76, (2),637 640 ). - 106.
Racke M. K. et al. 2000 The role of costimulation in autoimmune demyelination. , 107, (2),205 215 ). - 107.
Reynolds A. D. et al. 2007 Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. , 82, (5),1083 1094 ). - 108.
Reynolds A. D. et al. 2008a Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. , 104, (6),1504 1525 ). - 109.
Reynolds A. D. et al. 2008b Nitrated alpha-Synuclein and microglial neuroregulatory activities. ,54 74 ) - 110.
Reynolds A. D. et al. 2010 Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. , 184, (5),2261 2271 ). - 111.
Reynolds A. D. et al. 2009a Nitrated -synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. , 182, (7),4137 4149 ). - 112.
Reynolds A. D. et al. 2009b Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4+CD25+ T cells. , 8, (7),3497 3511 ). - 113.
Richter-Landsberg C. et al. 2000 alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. , 62, (1),9 14 ). - 114.
Roodveldt C. et al. 2009 Chaperone proteostasis in Parkinson’s disease: stabilization of the Hsp70/alpha-synuclein complex by Hip. , 28, (23),3758 3770 ). - 115.
Roodveldt C. et al. 2008 Immunological features of alpha-synuclein in Parkinson’s disease. , 12, (5B),1820 1829 ). - 116.
Roodveldt C. et al. 2010 Glial innate immunity generated by non-aggregated alpha-synuclein in mouse: differences between wild-type and Parkinson’s disease-linked mutants. , 5, (10),e13481 . - 117.
Rott R. et al. 2008 Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. , 283, (6),3316 3328 ). - 118.
Salazar-Mather T. P. et al. 1996 NK cell trafficking and cytokine expression in splenic compartments after IFN induction and viral infection. , 157, (7),3054 3064 ). - 119.
Sanchez-Guajardo V. et al. 2010 Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. , 5, (1),e8784 . - 120.
Sanchez-Pernaute R. et al. 2004 Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson’s disease. , 1, (1),6 . - 121.
Schiess M. C. et al. 2010 CSF from Parkinson disease patients differentially affects cultured microglia and astrocytes. , 11,151 . - 122.
Shin E. C. et al. 2000 Expression patterns of alpha-synuclein in human hematopoietic cells and in Drosophila at different developmental stages. , 10, (1),65 70 ). - 123.
Shults C. W. et al. 2005 Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. , 25, (46),10689 10699 ). - 124.
Souza J. M. et al. 2000 Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. , 275, (24),18344 18349 ). - 125.
Spillantini M. G. et al. 1998 alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. , 95, (11),6469 6473 ). - 126.
Stefani M. Dobson C. M. 2003 Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. , 81, (11),678 699 ). - 127.
Stone D. K. et al. 2009 Innate and adaptive immunity for the pathobiology of Parkinson’s disease. , 11, (9),2151 2166 ). - 128.
Su H. C. et al. 2001 NK cell functions restrain T cell responses during viral infections. , 31, (10),3048 3055 ). - 129.
Su X. et al. 2009 Mutant alpha-synuclein overexpression mediates early proinflammatory activity. , 16, (3),238 254 ). - 130.
Su X. et al. 2008 Synuclein activates microglia in a model of Parkinson’s disease. , 29, (11),1690 1701 ). - 131.
Tanji K. et al. 2002 Upregulation of alpha-synuclein by lipopolysaccharide and interleukin-1 in human macrophages. , 52, (9),572 577 ). - 132.
Tanji K. et al. 2001 Expression of beta-synuclein in normal human astrocytes. , 12, (13),2845 2848 ). - 133.
Terada S. et al. 2003 Glial involvement in diffuse Lewy body disease. , 105, (2),163 169 ). - 134.
Theodore S. et al. 2008 Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. , 67, (12),1149 1158 ). - 135.
Thomas M. P. et al. 2007 Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson’s disease. , 100, (2),503 519 ). - 136.
Tofaris G. K. et al. 2003 Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. , 278, (45),44405 44411 ). - 137.
Tokuda T. et al. 2006 Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson’s disease. , 349, (1),162 166 ). - 138.
Tokuda T. et al. 2010 Detection of elevated levels of -synuclein oligomers in CSF from patients with Parkinson disease. Neurol, 75, (20),1766 1772 ). - 139.
Verreck F. A. et al. 2004 Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. , 101, (13),4560 4565 ). - 140.
Vila M. et al. 2001 The role of glial cells in Parkinson’s disease. , 14, (4),483 489 ). - 141.
Wakabayashi K. et al. 2000 NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. , 99, (1),14 20 ). - 142.
Wersinger C. Sidhu A. 2006 An inflammatory pathomechanism for Parkinson’s disease? , 13, (5),591 602 ). - 143.
Wu D. C. et al. 2002 Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. , 22, (5),1763 1771 ). - 144.
Wyss-Coray T. Mucke L. 2002 Inflammation in neurodegenerative disease--a double-edged sword. , 35, (3),419 432 ). - 145.
Yamada T. et al. 1992 Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. , 84, (1),100 104 ). - 146.
Yazawa I. et al. 2005 Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. , 45, (6),847 859 ). - 147.
Yu S. et al. 2007 Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. , 145, (2),539 555 ). - 148.
Zarranz J. J. et al. 2004 The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. , 55, (2),164 173 ). - 149.
Zhang W. et al. 2007 Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein. , 55, (11),1178 1188 ). - 150.
Zhang W. et al. 2005 Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. , 19, (6),533 542 ). - 151.
Zhou Y. et al. 2005 Microglial activation induced by neurodegeneration: a proteomic analysis. , 4, (10),1471 1479 ).