**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 [32–35]. 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].
