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

#### **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, 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 complex to the plasma membrane, where Axin directly binds to the cytoplasmic tail of the lowdensity 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 betacatenin 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, [21–23]. 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 dyspla‐ sia/cardiomyopathy (ARVC) and certain NDs [8].
