Open access peer-reviewed chapter

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

Written By

Yves Lecarpentier and Alexandre Vallée

Submitted: 15 November 2015 Reviewed: 17 March 2016 Published: 14 September 2016

DOI: 10.5772/63152

From the Edited Volume

Update on Amyotrophic Lateral Sclerosis

Edited by Humberto Foyaca Sibat and Lourdes de Fatima Ibañez Valdés

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Abstract

Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset debilitating neurodegenerative diseases (NDs) which is characterized by a chronic progressive degeneration of upper and lower motor neurons, resulting in muscular atrophy, paralysis and ultimately death. It has been established that in ALS, the canonical Wnt/beta-catenin pathway is upregulated. Peroxisome proliferator-activated receptor gamma (PPAR gamma) generally varies in opposite way compared with the Wnt/beta-catenin signaling. Several studies carried out on ALS transgenic mice have shown the beneficial effects induced after treatment by PPAR agonists partly due to anti-inflammatory effects induced by PPAR gamma. The coupling between the Wnt/beta-catenin signaling and PPAR gamma has led to divide NDs into two classes: NDs in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregulated (ALS, Parkinson’s disease, Huntington’s disease and Friedreich’s ataxia); and NDs in which the Wnt-beta-catenin pathway is downregulated while PPAR gamma is upregulated (Alzheimer’s disease, bipolar disorder and schizophrenia).

Keywords

  • Wnt/beta-catenin
  • PPAR gamma
  • amyotrophic lateral sclerosis
  • riluzole
  • ALS

1. Introduction

Neurodegenerative diseases (NDs) are frequent and often present a pejorative prognosis. Two major systems play a key role in the pathophysiology of NDs, i.e., the canonical Wnt/beta-catenin pathway and PPAR gamma. Several studies have demonstrated the opposite interaction between the canonical Wnt/beta-catenin pathway and the PPAR gamma [17]. It has recently been shown that certain NDs can be divided into two classes [8]: on one hand, NDs in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregulated. Among these NDs, we find amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease and Friedreich’s ataxia. PPAR agonists exert protective effects in ALS neurons of transgenic mice and may represent therapeutic targets in human ALS. On the other hand, NDs in which the Wnt-beta-catenin pathway is downregulated while PPAR gamma is upregulated. Among these NDs, we find Alzheimer’s disease, bipolar disorder and schizophrenia. This list is not exhaustive.

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2. Amyotrophic lateral sclerosis (ALS)

ALS is one of the most common adult-onset debilitating NDs with the prevalence of about 5 per 100,000 individuals. The pathophysiology of ALS in humans is particularly complex, due to the numerous interconnected pathological processes and, today, has not been fully elucidated. However, it remains to determine those really responsible for the disease from those simply involved in its development. ALS has been first described by J.M. Charcot in 1869. ALS is a fatal neurodegenerative disorder and is characterized by chronic progressive degeneration of upper and lower motor neurons, resulting in muscular atrophy, paralysis and ultimately death. And, 82% of ALS are sporadic. The most frequent mutations in inherited or familial ALS (FALS) are found in the gene for Cu, Zn superoxide dismutase (SOD1). Among numerous abnormalities, this FALS presents glutamate toxicity, axonal transport defects, aberrant neurotrophic factors, mitochondrial dysfunction [9]. Numerous in vivo studies have used transgenic mice expressing FALS mutants of human SOD1 [10]. This transgenic model develops a progressive motor neuron pathology which is reminiscent of the human ALS phenotype [11]. The human sporadic ALS differs little clinically from SOD1-related FALS. Both forms of ALS induce degeneration of motor neurons which leads to paralysis and death within 3–5 years from the appearance of the first symptoms. Today, no pharmacological therapeutic can really stop the progression of the disease. Although riluzole is approved for ALS patients, the benefits of this drug are marginal [1215].

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3. Canonical Wnt/beta-catenin pathway

Wnt signaling plays a key role in carcinogenesis, embryonic development, cell fate, cell migration and NDs [16, 17]. A hallmark of the canonical Wnt pathway activation by Wnt ligands is the increase in the cytoplasmic beta-catenin protein level, the subsequent nuclear translocation and further activation of beta-catenin specific gene transcription [4, 1820]. In the absence of Wnt ligands, beta-catenin is recruited into a destruction complex that contains adenomatous polyposis coli (APC) and Axin, which facilitate the phosphorylation of beta-catenin by glycogen synthase kinase-3beta (GSK-3beta). GSK-3beta phosphorylates the N-terminal domain of beta-catenin, thereby targeting it for ubiquitination and proteasomal degradation. In the presence of a Wnt ligand, the binding of Wnt to Frizzled (Fzd) leads to activation of the phosphoprotein Dishevelled (Dsh). Dsh recruits Axin and the destruction complex to the plasma membrane, where Axin directly binds to the cytoplasmic tail of the low-density lipoprotein-receptor-related proteins (LRP5-6). The activation of Dsh also leads to the inhibition of GSK-3beta by phosphorylation, which further reduces the phosphorylation and degradation of beta-catenin. The beta-catenin degradation complex is inactivated with recruitment of Axin to the plasma membrane, thus stabilizing the non-phosphorylated beta-catenin which translocates to the nucleus. Beta-catenin binds to T cell/lymphoid-enhancing binding (Tcf/Lef) transcription factors. The resulting complex becomes active by displacing Grouchos, leading to activation of numerous target genes including c-myc, cyclin D1, TIFF-1, Axin-2, CD44, Cox2, MMP-7, PPAR beta/delta, [2123]. Upregulation of the canonical Wnt/beta-catenin pathway is observed in metabolic diseases such as type 2 diabetes, hypertension, in cancers (colon, lung, breast, leukemias) and certain NDs. Downregulation is observed in osteoporosis, cardiac hypoxia, cardiac hypertrophy, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) and certain NDs [8].

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4. PPAR gamma

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. PPAR gamma regulates the expression or activity of a large number of genes in a variety of signaling pathways, including regulation of insulin sensitivity, glucose homeostasis, lipid metabolism, immune responses, inflammation, redox balance, cardiovascular integrity and cell fate [24, 25]. PPAR gamma is expressed in various cell types, such as adipose tissues, immune cells and brain cells including microglia and astrocytes which contribute to anti-inflammatory response in the central nervous system. During the past decade, the role of PPAR gamma in neurodegeneration has been established. The administration of PPAR gamma ligands has been shown to be beneficial in many NDs such as ALS, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease and stroke [26]. PPAR gamma has been shown to have anti-inflammatory and neuroprotective effects [27, 28]. Astrocytic GLT1/EAAT2 gene is a target of PPAR gamma, leading to neuroprotection by increasing the glutamate uptake [29]. PPAR gamma is a direct transcriptional modulator of the pyruvate carboxylase gene [30]. Given the fact that ALS patients suffer from massive weight loss, this provides a possible explanation for the potential protective effects of pioglitazone through increased lipogenesis.

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5. PPAR gamma activation induces repression of the beta-catenin pathway

The thiazolidinedione PPAR gamma agonists (TZDs), troglitazone, rosiglitazone and pioglitazone, and a non-thiazolidinedione PPAR gamma activator, GW1929, inhibit the beta-catenin-induced transcription in a PPAR gamma-dependent fashion [13, 5]. Troglitazone-mediated activation of PPAR gamma is associated with an inhibition of beta-catenin at a post-transcriptional level. The functional interaction between beta-catenin and PPAR gamma involves the Tcf/Lef factor-binding domain of beta-catenin and a catenin-binding domain within PPAR gamma [5]. Treatment with PPAR gamma agonists decreases mRNA and protein levels of beta-catenin in 3T3L1 adipocytes [1]. TZDs induce a reduction in the levels of cytoplasmic beta-catenin in hepatocytes [3]. PPAR gamma suppresses Wnt/beta-catenin pathway during adipogenesis [2].

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6. Deactivation of the Wnt/beta-catenin pathway induces activation of PPAR gamma

Inhibition of Wnt/beta-catenin pathway leads to an increase in transcription of PPAR gamma. Activation of the Wnt/beta-catenin signaling leads to osteogenesis, but not to adipogenesis. The canonical Wnt/beta-catenin-PPAR gamma system regulates the molecular switching of osteablastogenesis versus adipogenesis [6]. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of both adipogenic transcription factors C/EBP alpha and PPAR gamma. Deactivation of Wnt/beta catenin pathway and activation of PPAR gamma are observed in ARVD [4, 31]. Taken together, these studies suggest that the canonical Wnt/beta-catenin signaling downregulates PPAR gamma expression, inhibition of Wnt/beta-catenin signaling upregulates PPAR gamma expression and PPAR gamma agonists inhibit the canonical Wnt/beta-catenin pathway.

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7. ALS and Wnt/beta-catenin pathway

The canonical Wnt/beta-catenin signaling is involved in numerous NDs, particularly in ALS. Several studies have shown that this pathway is upregulated in motor neurons of ASL model mice [3235]. In the spinal cord of SOD1(G93A) ALS transgenic mice, expression of Wnt2, Wnt7a and GSK-3beta has been determined [32]. Both Wnt2, Wnt7a mRNA and protein in the spinal cord of ALS mice have been found to be upregulated when compared with wild type. The immune-reactivity of Wnt2 and Wnt7a is strong in ALS adult transgenic mice, whereas it is weak in wild-type mice. Neurodegeneration upregulates the expression of Wnt2 and Wnt7a in the spinal cord of ALS mice, which in turn activates Wnt signaling and inhibits GSK-3beta activity in ALS adult transgenic mice. Expression of Wnt3a, beta-catenin and Cyclin D1, three key molecules of the Wnt/beta-catenin signaling, have been determined in the adult spinal cord of SOD1(G93A) ALS transgenic mice at different stages [33]. It has been found that mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice are upregulated compared with wild-type mice. Moreover, beta-catenin translocates from the cell membrane to the nucleus and subsequently activated transcription of the target gene Cyclin D1. Wnt3a, beta-catenin and Cyclin D1 are also expressed in both neurons and astrocytes. For the authors, these findings suggest that neurodegeneration activates the Wnt/beta-catenin pathway, in the spinal cord of adult ALS transgenic mice. Changes in Wnt5a and Fzd2 expression in the spinal cord of SOD1(G93A) transgenic mice (ALS), SOD1(G93A) transfected NSC-34 cells and primary cultures of astrocytes from SOD1(G93A) transgenic mice have been observed [35]. Expression of Wnt1 and Fzd1 has been found to be increased in the spinal cords of SOD1G93A ALS transgenic mice [34]. In the in vitro model of ALS (G93A mutated forms of human Cu/Zn superoxide dismutase-1; SOD1), a cytosolic aggregation of beta-catenin has been observed. This suggests that Wnt/beta-catenin pathway could play critical role in the neurodegeneration of motor neurons in ALS [36]. Beta-catenin is activated in a subset of myofibers in extraocular muscles and limb muscles in ALS subjects [37].

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8. ALS and riluzole

Today, no really efficient treatment exists for ALS [38, 39]. However, riluzole has been approved for the treatment of ALS in most countries and is tested in people based on results supporting a role of glutamate toxicity in ALS. Riluzole has numerous pharmacodynamics properties, i.e., presynaptic inhibition of the glutamate release, inhibition of G-protein-dependent processes, modulation of N-methyl-D-aspartate ionotropic receptor and blockade of the voltage-gated sodium channel, etc. [39]. Two trials [12, 13] have demonstrated the weak efficacy of riluzole in ALS with prolongation of median survival by 2 to 3 months and safety of riluzole. Thus, riluzole appears to slow the progression of ALS, and may improve survival in patients with disease of bulbar onset [12]. Riluzole is well tolerated and lengthens survival of patients with ALS [13]. Two other studies have led to almost the same conclusions [14, 15]. The FDA-approved drug, riluzole, 100 mg daily is reasonably safe and probably prolongs median survival by about 2 to 3 months in patients with ALS.

Importantly, riluzole has been found to be an enhancer of the Wnt/beta-catenin signaling in melanoma [40]. For the authors, treating melanoma cells with riluzole in vitro enhances the ability of WNT3A to regulate gene expression, promote pigmentation and decrease cell proliferation. Like WNT3A, riluzole decreases metastases in a mouse melanoma model. Moreover, riluzole enhances Wnt/beta-catenin signaling in the primary screen both in HT22 neuronal cells and in adult hippocampal progenitor cells [40]. As the Wnt/beta-catenin pathway is upregulated, at least in genetic ALS mice [3235], this can partly explain poor results in trials testing riluzole in ALS as shown previously [1215]. Lithium, an activator of the Wnt/beta catenin signaling, has also been evaluated as a treatment for ALS [41]. Surprisingly, in ALS patients treated with lithium, the disease progression has been shown to be markedly attenuated. In the genetic ALS G93A mouse model, there is a marked neuroprotection induced by lithium, which delayed disease onset and duration and augmented the life span. The use of the enhancer Wnt/beta-catenin lithium can be discussed in ALS in which the Wnt/beta-catenin pathway has been shown to be upregulated in several animal studies [3235]. GSK-3beta-inhibitor lithium chloride enhances activation of the canonical Wnt signaling [4244]. Lithium activates downstream components of the Wnt signaling pathway in vivo, leading to an increase of the beta-catenin protein. This pathway is implicated in the pathophysiology and treatment of bipolar disorder [45, 46]. Riluzole reduces symptoms of obsessive-compulsive disorder, unipolar and bipolar depression and generalized anxiety disorder [47]. This is not surprising due to the fact that the Wnt/beta-catenin pathway is downregulated in bipolar syndrome [8] and that like lithium, riluzole is an enhancer of Wnt/beta-catenin signaling.

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9. ALS and PPAR gamma

In ALS, expression of PPAR gamma (mARN and protein) has not been precisely investigated in neurons. However, the upregulation of Wnt/beta-catenin signaling observed in ALS suggests that PPAR gamma might be downregulated due to the fact that these two systems generally operate in the opposite way [13, 5]. Neuroinflammation is a common pathological feature in NDs, particularly in ALS. PPAR gamma may be a key regulator of neuroinflammation. PPAR gamma inhibits NF-kappaB-mediated inflammatory signaling at multiple sites [48]. PPAR gamma might be a relevant regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. A potentially therapeutic pathway in ALS may be the activation by PPAR gamma agonists due to their ability to block neuropathological damages caused by inflammation [49]. The neuroprotective effect of pioglitazone has been demonstrated in G93A SOD1 transgenic mouse model of ALS and shows a significant increase in their survival. Pioglitazone protects motor neurons against p38-mediated neuronal death and NF-kappaB-mediated glial inflammation via a PPAR gamma-independent mechanism [50]. In ALS, PPAR gamma controls natural protective mechanisms against lipid peroxidation [51]. PPAR gamma-driven transcription selectively increases in the spinal cord of hSOD1G93A mice. This is correlated with the upregulation of lipid detoxification enzymes such as the lipoprotein lipase and glutathione S-transferase alpha-2, implied in scavenging lipid peroxidation by-products. Anticipation of protective reactions by pharmacological PPAR gamma modulation of the transcriptional activity attenuates neurodegeneration induced by lipid peroxidation. PPAR gamma activation is neuroprotective in a Drosophila model of ALS [52]. This Drosophila model of ALS based on TDP-43 recapitulates several aspects of ALS pathophysiology. Pioglitazone rescues TDP-43-dependent locomotor dysfunction in motor neurons and glia. PPAR gamma activation in neurons and glia is partially neuroprotective and restores metabolic alterations in ALS. Superoxide dismutase (SOD1)-G93A transgenic mice benefit from oral treatment with the PPAR gamma agonist pioglitazone [53]. Pioglitazone-treated transgenic mice reveal improved muscle strength and body weight, exhibit a delayed disease onset and survive significantly longer than non-treated SOD1-G93A mice. Pioglitazone-induced neuroprotection of motor neurons of the spinal cord is complete at day 90. There is also preservation of the median fiber diameter of the quadriceps muscle, indicating a morphological and functional protection of motor neurons induced by pioglitazone. However, in a phase II double-blind controlled clinical trial, the PPAR gamma agonist pioglitazone in combination with riluzole does not increase survival in ALS patients [54].

PPAR gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that works together with the transcription factor PPAR gamma in the regulation of mitochondrial biogenesis. PGC-1alpha plays a role in several neurodegenerative pathologies [26]. PGC-1alpha protects neurons and alters disease progression in a PGC-1alpha transgenic mice crossed with SOD1 mutant G93A DL mice [55]. In these mice, the progression of the disease has been shown to be significantly slower. There is also a markedly improved performance on the rotarod test associated with an improved motor activity with a decreased loss of motor neurons and less degeneration of neuromuscular junctions. By using a double transgenic mouse model where PGC-1alpha is over-expressed in a SOD1 transgenic mouse (TgSOD1-G93A/PGC-1alpha), it has been found that motor function and survival are improved [56]. This is accompanied by a reduction of motor neuron loss, a restoration of mitochondrial electron transport chain activities and an inhibition of stress signaling in the spinal cord. Thus, in the double-transgenic mice, there are improved motor performance, slowed ALS progression, decreased weight loss, and reduced motor neuronal death. Survival and disease improvement are greater in higher-expressing PGC-1alpha mice. Therefore, PPAR gamma is a possible target for ALS as it functions as a transcription factor that interacts with PGC-1alpha. Elevated PGC-1alpha activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS [57]. Increasing PGC-1alpha activity in muscles represents an attractive therapy for maintaining muscle function during the progression of ALS.

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10. Conclusions

PPAR agonists represent promising therapeutics for NDs such as multiple sclerosis, ALS and Alzheimer’s disease (AD). Their activation affects many pathological mechanisms. PPAR activation can weaken or reprogram the immune response, stimulate metabolism, improve mitochondrial function, promote axon growth and induce progenitor cells to differentiate into myelinating oligodendrocytes [58]. The mechanisms of action of PPAR agonists are various and may be useful at many stages of diseases. Type, timing and dose of PPAR agonists may vary depending on injury severity, progression of disease or cellular targets such as neurons, microglia, oligodendrocytes, and may explain a number of conflicting results in several studies. PPAR gamma may be useful due to its anti-inflammatory properties. Moreover, PPAR gamma agonists induce beta-catenin inhibition [3, 5], which represents a rationale to use it when the Wnt/beta-catenin pathway is upregulated such as in Parkinson’s disease, multiple sclerosis, ALS, Huntington's disease and Friedreich's ataxia [8]. However, in AD, PPAR gamma levels (mRNA and protein) have been found to be elevated in brain tissues [59, 60]. Although PPAR gamma expression is high in AD, PPAR gamma agonists have been used in AD humans and various AD animal models and have been shown to induce beneficial effects, partly due to their anti-inflammatory effects [6167]. Even if the PPAR gamma agonist pioglitazone, in combination with riluzole, does not increase survival in ALS patients [54], PPAR gamma represents a useful therapeutic target in several animal models. Inhibition of the Wnt/beta-catenin pathway might also represent a therapeutic approach in ALS animal model.

Acknowledgments

We thank Dr Michel Grivaux, Director of the Clinical Research Center, Meaux Hospital, and Mr Vincent Gobert, Administrative Manager of the Clinical Research Center, Meaux hospital, France.

References

  1. 1. Gerhold DL, Liu F, Jiang G, Li Z, Xu J, Lu M, Sachs JR, Bagchi A, Fridman A, Holder DJ et al.: Gene expression profile of adipocyte differentiation and its regulation by peroxisome proliferator-activated receptor-gamma agonists. Endocrinology 2002, 143(6):2106–2118. DOI: 10.1210/endo.143.6.8842
  2. 2. Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, Farmer SR: Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochemistry journal 2003, 376(Pt 3):607–613.
  3. 3. Sharma C, Pradeep A, Wong L, Rana A, Rana B: Peroxisome proliferator-activated receptor gamma activation can regulate beta-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway. The journal of biological chemistry 2004, 279(34):35583–35594. DOI: 10.1074/jbc.M403143200
  4. 4. Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ: Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. The journal of clinical investigation 2006, 116(7):2012–2021.
  5. 5. Liu J, Wang H, Zuo Y, Farmer SR: Functional interaction between peroxisome proliferator-activated receptor gamma and beta-catenin. Molecular and cellular biology 2006, 26(15):5827–5837. DOI: 26/15/5827 [pii]10.1128/MCB.00441-06
  6. 6. Takada I, Kouzmenko AP, Kato S: Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol 2009, 5(8):442–447.
  7. 7. Lu D, Carson DA: Repression of beta-catenin signaling by PPAR gamma ligands. European journal of pharmacology 2010, 636(1–3):198–202. DOI: 10.1016/j.ejphar.2010.03.010
  8. 8. Lecarpentier Y, Claes V, Duthoit G, Hebert JL: Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction. Front physiology 2014, 5:429. DOI: 10.3389/fphys.2014.00429
  9. 9. Redler RL, Dokholyan NV: The complex molecular biology of amyotrophic lateral sclerosis (ALS). Progress in molecular biologyand translational science 2012, 107:215–262. DOI: 10.1016/B978-0-12-385883-2.00002-3
  10. 10. Rosen DR: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 364(6435):362. DOI: 10.1038/364362c0
  11. 11. Turner BJ, Talbot K: Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Progress in neurobiology 2008, 85(1):94–134. DOI: 10.1016/j.pneurobio.2008.01.001
  12. 12. Bensimon G, Lacomblez L, Meininger V: A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. The New England journal of medicine 1994, 330(9):585–591. DOI: 10.1056/NEJM199403033300901
  13. 13. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V: Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 1996, 347(9013):1425–1431.
  14. 14. Miller RG, Mitchell JD, Lyon M, Moore DH: Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotrophic lateral sclerosis and other motor neuron disorders: official publication of the world federation of neurology, research group on motor neuron diseases 2003, 4(3):191–206.
  15. 15. Miller RG, Mitchell JD, Moore DH: Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). The Cochrane database of systematic reviews 2012, 3:CD001447. DOI: 10.1002/14651858.CD001447.pub3
  16. 16. Moon RT, Kohn AD, De Ferrari GV, Kaykas A: WNT and beta-catenin signalling: diseases and therapies. Nature review genetics 2004, 5(9):691–701. DOI: 10.1038/nrg1427
  17. 17. Clevers H, Nusse R: Wnt/beta-catenin signaling and disease. Cell 2012, 149(6):1192–1205. DOI: 10.1016/j.cell.2012.05.012
  18. 18. Barker N, Clevers H: Mining the Wnt pathway for cancer therapeutics. Nature review drug discovery 2006, 5(12):997–1014. DOI: 10.1038/nrd2154
  19. 19. Ben-Ze'ev A, Geiger B: Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer. Current opinions in cellular biology 1998, 10(5):629–639. DOI: S0955-0674(98)80039-2 [pii]
  20. 20. Sen-Chowdhry S, Syrris P, McKenna WJ: Genetics of right ventricular cardiomyopathy. Journal of cardiovascular electrophysiology 2005, 16(8):927–935. DOI: JCE40842 [pii]
  21. 21. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW: Identification of c-MYC as a target of the APC pathway. Science 1998, 281(5382):1509–1512.
  22. 22. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A: The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proceedings of the national academy of sciences of the United States of America 1999, 96(10):5522–5527.
  23. 23. Angers S, Moon RT: Proximal events in Wnt signal transduction. Nature reviews molecular cell biology 2009, 10(7):468–477. DOI: 10.1038/nrm2717
  24. 24. Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz M, Moller DE, Berger J: Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. Biochemical and biophysical research communications 1996, 224(2):431–437.
  25. 25. Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S et al.: The organization, promoter analysis, and expression of the human PPARgamma gene. The journal of biological chemistry 1997, 272(30):18779–18789.
  26. 26. Katsouri L, Blondrath K, Sastre M: Peroxisome proliferator-activated receptor-gamma cofactors in neurodegeneration. IUBMB life 2012, 64(12):958–964. DOI: 10.1002/iub.1097
  27. 27. Kapadia R, Yi JH, Vemuganti R: Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Frontiers in bioscience: a journal and virtual library 2008, 13:1813–1826.
  28. 28. Gray E, Ginty M, Kemp K, Scolding N, Wilkins A: The PPAR-gamma agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function. Journal of neuroinflammation 2012, 9:63. DOI: 10.1186/1742-2094-9-63
  29. 29. Romera C, Hurtado O, Mallolas J, Pereira MP, Morales JR, Romera A, Serena J, Vivancos J, Nombela F, Lorenzo P et al.: Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPARgamma target gene involved in neuroprotection. Journal of cerebral blood flow and metabolism: official journal of the international society of cerebral blood flow and metabolism 2007, 27(7):1327–1338. DOI: 10.1038/sj.jcbfm.9600438
  30. 30. Jitrapakdee S, Slawik M, Medina-Gomez G, Campbell M, Wallace JC, Sethi JK, O'Rahilly S, Vidal-Puig AJ: The peroxisome proliferator-activated receptor-gamma regulates murine pyruvate carboxylase gene expression in vivo and in vitro. The journal of biological chemistry 2005, 280(29):27466–27476. DOI: 10.1074/jbc.M503836200
  31. 31. Djouadi F, Lecarpentier Y, Hebert JL, Charron P, Bastin J, Coirault C: A potential link between PPAR signaling and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Cardiovascular research 2009,84:83–90.
  32. 32. Chen Y, Guan Y, Zhang Z, Liu H, Wang S, Yu L, Wu X, Wang X: Wnt signaling pathway is involved in the pathogenesis of amyotrophic lateral sclerosis in adult transgenic mice. Neurological research 2012, 34(4):390–399. DOI: 10.1179/1743132812Y.0000000027
  33. 33. Chen Y, Guan Y, Liu H, Wu X, Yu L, Wang S, Zhao C, Du H, Wang X: Activation of the Wnt/beta-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice. Biochemical and biophysical research communications 2012, 420(2):397–403. DOI: 10.1016/j.bbrc.2012.03.006
  34. 34. Wang S, Guan Y, Chen Y, Li X, Zhang C, Yu L, Zhou F, Wang X: Role of Wnt1 and Fzd1 in the spinal cord pathogenesis of amyotrophic lateral sclerosis-transgenic mice. Biotechnology Letters 2013, 35(8):1199–1207. DOI: 10.1007/s10529-013-1199-1
  35. 35. Li X, Guan Y, Chen Y, Zhang C, Shi C, Zhou F, Yu L, Juan J, Wang X: Expression of Wnt5a and its receptor Fzd2 is changed in the spinal cord of adult amyotrophic lateral sclerosis transgenic mice. International journal of clinical and. experimental pathology 2013, 6(7):1245–1260.
  36. 36. Pinto C, Cardenas P, Osses N, Henriquez JP: Characterization of Wnt/beta-catenin and BMP/Smad signaling pathways in an in vitro model of amyotrophic lateral sclerosis. Frontiers in cellular neuroscience 2013, 7:239. DOI: 10.3389/fncel.2013.00239
  37. 37. McLoon LK, Harandi VM, Brannstrom T, Andersen PM, Liu JX: Wnt and extraocular muscle sparing in amyotrophic lateral sclerosis. Investigative ophthalmology & visual science 2014, 55(9):5482–5496. DOI: 10.1167/iovs.14-14886
  38. 38. Carter GT, Krivickas LS, Weydt P, Weiss MD, Miller RG: Drug therapy for amyotrophic lateral sclerosis: where are we now? IDrugs: the investigational drugs journal 2003, 6(2):147–153.
  39. 39. Aggarwal S, Cudkowicz M: ALS drug development: reflections from the past and a way forward. Neurotherapeutics: the journal of the American society for experimental neurotherapeutics 2008, 5(4):516–527. DOI: 10.1016/j.nurt.2008.08.002
  40. 40. Biechele TL, Camp ND, Fass DM, Kulikauskas RM, Robin NC, White BD, Taraska CM, Moore EC, Muster J, Karmacharya R et al.: Chemical-genetic screen identifies riluzole as an enhancer of Wnt/beta-catenin signaling in melanoma. Chemistry & biology 2010, 17(11):1177–1182. DOI: 10.1016/j.chembiol.2010.08.012
  41. 41. Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P et al.: Lithium delays progression of amyotrophic lateral sclerosis. Proceedings of the national academy of sciences of the United States of America 2008, 105(6):2052–2057. DOI: 10.1073/pnas.0708022105
  42. 42. Hedgepeth CM, Conrad LJ, Zhang J, Huang HC, Lee VM, Klein PS: Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Developmental biology 1997, 185(1):82–91. DOI: 10.1006/dbio.1997.8552
  43. 43. Sinha D, Wang Z, Ruchalski KL, Levine JS, Krishnan S, Lieberthal W, Schwartz JH, Borkan SC: Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors. American journal of physiology renal physiology 2005, 288(4):F703–713. DOI: 10.1152/ajprenal.00189.2004
  44. 44. Galli C, Piemontese M, Lumetti S, Manfredi E, Macaluso GM, Passeri G: GSK3b-inhibitor lithium chloride enhances activation of Wnt canonical signaling and osteoblast differentiation on hydrophilic titanium surfaces. Clinical oral implants research 2013, 24(8):921–927. DOI: 10.1111/j.1600-0501.2012.02488.x
  45. 45. Gould TD, Manji HK: The Wnt signaling pathway in bipolar disorder. Neuroscientist 2002, 8(5):497–511.
  46. 46. Valvezan AJ, Klein PS: GSK-3 and Wnt signaling in neurogenesis and bipolar disorder. Front Mol Neurosci 2012, 5:1. DOI: 10.3389/fnmol.2012.00001
  47. 47. Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G: Riluzole in the treatment of mood and anxiety disorders. CNS drugs 2008, 22(9):761–786.
  48. 48. Chen YC, Wu JS, Tsai HD, Huang CY, Chen JJ, Sun GY, Lin TN: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) and neurodegenerative disorders. Molecular neurobiology 2012, 46(1):114–124. DOI: 10.1007/s12035-012-8259-8
  49. 49. Kiaei M: Peroxisome proliferator-activated receptor-gamma in amyotrophic lateral sclerosis and Huntington’s disease. PPAR research 2008, 2008:418765.
  50. 50. Shibata N, Kawaguchi-Niida M, Yamamoto T, Toi S, Hirano A, Kobayashi M: Effects of the PPARgamma activator pioglitazone on p38 MAP kinase and IkappaBalpha in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis. Neuropathology: official journal of the Japanese society of neuropathology 2008, 28(4):387–398. DOI: 10.1111/j.1440-1789.2008.00890.x
  51. 51. Benedusi V, Martorana F, Brambilla L, Maggi A, Rossi D: The peroxisome proliferator-activated receptor gamma (PPARgamma) controls natural protective mechanisms against lipid peroxidation in amyotrophic lateral sclerosis. The journal of biological chemistry 2012, 287(43):35899–35911. DOI: 10.1074/jbc.M112.366419
  52. 52. Joardar A, Menzl J, Podolsky TC, Manzo E, Estes PS, Ashford S, Zarnescu DC: PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. Human molecular genetics 2015, 24(6):1741–1754. DOI: 10.1093/hmg/ddu587
  53. 53. Schutz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE, Schurmann B, Zimmer A, Heneka MT: The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. The journal of neuroscience: the official journal of the society for neuroscience 2005, 25(34):7805–7812. DOI: 10.1523/JNEUROSCI.2038-05.2005
  54. 54. Dupuis L, Dengler R, Heneka MT, Meyer T, Zierz S, Kassubek J, Fischer W, Steiner F, Lindauer E, Otto M et al.: A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PloS one 2012, 7(6):e37885. DOI: 10.1371/journal.pone.0037885
  55. 55. Liang H, Ward WF, Jang YC, Bhattacharya A, Bokov AF, Li Y, Jernigan A, Richardson A, Van Remmen H: PGC-1alpha protects neurons and alters disease progression in an amyotrophic lateral sclerosis mouse model. Muscle nerve 2011, 44(6):947–956. DOI: 10.1002/mus.22217
  56. 56. Zhao W, Varghese M, Yemul S, Pan Y, Cheng A, Marano P, Hassan S, Vempati P, Chen F, Qian X et al.: Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1alpha) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis. Molecular neurodegeneration 2011, 6(1):51. DOI: 10.1186/1750-1326-6-51
  57. 57. Da Cruz S, Parone PA, Lopes VS, Lillo C, McAlonis-Downes M, Lee SK, Vetto AP, Petrosyan S, Marsala M, Murphy AN et al.: Elevated PGC-1alpha activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell metabolism 2012, 15(5):778–786. DOI: 10.1016/j.cmet.2012.03.019
  58. 58. Mandrekar-Colucci S, Sauerbeck A, Popovich PG, McTigue DM: PPAR agonists as therapeutics for CNS trauma and neurological diseases. ASN neuro 2013, 5(5):e00129. DOI: 10.1042/AN20130030
  59. 59. Kitamura Y, Shimohama S, Koike H, Kakimura J, Matsuoka Y, Nomura Y, Gebicke-Haerter PJ, Taniguchi T: Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer’s disease brains. Biochemical and biophysical research communications 1999, 254(3):582–586.
  60. 60. de la Monte SM, Wands JR: Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. Journal of Alzheimer’s disease 2006, 9(2):167–181.
  61. 61. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE: Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. The journal of neuroscience: the official journal of the society for neuroscience 2000, 20(2):558–567.
  62. 62. Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT: Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. The journal of neuroscience: the official journal of the society for neuroscience 2003, 23(30):9796–9804.
  63. 63. Camacho IE, Serneels L, Spittaels K, Merchiers P, Dominguez D, De Strooper B: Peroxisome-proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. The journal of neuroscience: the official journal of the society for neuroscience 2004, 24(48):10908–10917. DOI: 10.1523/JNEUROSCI.3987-04.2004
  64. 64. d'Abramo C, Massone S, Zingg JM, Pizzuti A, Marambaud P, Dalla Piccola B, Azzi A, Marinari UM, Pronzato MA, Ricciarelli R: Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death. Biochemistry journal 2005, 391(Pt 3):693–698. DOI: 10.1042/BJ20050560
  65. 65. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR: Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Experimental neurology 2006, 199(2):265–273. DOI: 10.1016/j.expneurol.2006.01.018
  66. 66. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD: Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics journal 2006, 6(4):246–254. DOI: 10.1038/sj.tpj.6500369
  67. 67. Escribano L, Simon AM, Gimeno E, Cuadrado-Tejedor M, Lopez de Maturana R, Garcia-Osta A, Ricobaraza A, Perez-Mediavilla A, Del Rio J, Frechilla D: Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology: official publication of the American college of neuropsychopharmacology 2010, 35(7):1593–1604. DOI: 10.1038/npp.2010.32

Written By

Yves Lecarpentier and Alexandre Vallée

Submitted: 15 November 2015 Reviewed: 17 March 2016 Published: 14 September 2016