| Summary: | Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disease with considerable variability in the disease course even in familial cases associated with autosomal dominant SOD1 gene mutations. Previously, we have shown that SOD1G93A mice, the most widely used model of ALS, exhibit remarkable variability in disease onset and progression according to the mouse genetic background used (Pizzasegola et al 2009). The overall aim of this thesis was to explain the phenotype diversity between two SODIG93A mouse strains on C57BLl6J and 129S2ISv backgrounds since they carry the same number of human SODl transgene copies and express the same amount of mutant SODl mRNA and protein. We found that the levels of insoluble proteins greatly differ between the two SODIG93A mouse strains. In the lumbar spinal cord, the mice with fast disease progression (129SvG93A) exhibited an earlier and higher accumulation of ubiquitinated protein aggregates, mutant-SOD! and several chaperone proteins in comparison with the slowly progressing mice (C57G93A). In contrast, the levels of insoluble TDP43 and its phosphorylated form were higher in the slow than in the fast progressing mice. This led us to perform an in depth investigation of the protein quality control pathways during the course of the disease in these two mouse strains. In the lumbar spinal cord, the fast progressing mice showed lower expression of the chaperone αBcrystallin and an earlier reduction 0[' all the catalytic subunits of the proteasome compared to the slow progressing mice. However, a later induced expression of proteins involved in the misfolded protein recoguition complex and autophagic degradation, such as HspBS, Bag3 and the soluble Hsc70 was observed in the 129SvG93A mice. These data emphasize the involvement of impaired protein quality control mechanisms, in particular the chaperones and proteasome, in determining a more aggressive disease course in in vivo models of ALS.
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