**4. PPAR gamma**

in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregu‐ lated. 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 schizo‐

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 eluci‐ dated. 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,

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, 18–20]. 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 betacatenin by glycogen synthase kinase-3beta (GSK-3beta). GSK-3beta phosphorylates the Nterminal 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

phrenia. This list is not exhaustive.

258 Update on Amyotrophic Lateral Sclerosis

**2. Amyotrophic lateral sclerosis (ALS)**

the benefits of this drug are marginal [12–15].

**3. Canonical Wnt/beta-catenin pathway**

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 neurode‐ generation 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 antiinflammatory 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.

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

The thiazolidinedione PPAR gamma agonists (TZDs), troglitazone, rosiglitazone and piogli‐ tazone, and a non-thiazolidinedione PPAR gamma activator, GW1929, inhibit the beta-catenininduced transcription in a PPAR gamma-dependent fashion [1–3, 5]. Troglitazone-mediated activation of PPAR gamma is associated with an inhibition of beta-catenin at a post-transcrip‐ tional 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 betacatenin in 3T3L1 adipocytes [1]. TZDs induce a reduction in the levels of cytoplasmic betacatenin in hepatocytes [3]. PPAR gamma suppresses Wnt/beta-catenin pathway during adipogenesis [2].
