Motor neuronal and muscle selective removal of ALS-related misfiled proteins

Amyotrophic lateral sclerosis (ALS), a fatal motoneuron disease, occurs in clinically indistinguishable sporadic (sALS) or familial (fALS) forms. Most fALS-related mutant proteins are prone to misfold. They must be cleared from cells with the assistance of chaperones, via proteasome (UPS) or autophagic systems. Motoneurons are very sensitive to misfolded protein toxicity, but other cell types could also be affected. For example, muscle-restricted expression of mutant superoxide dismutase 1 (mutSOD1), responsible for some fALS, induces muscle atrophy and motoneurons death. We found several genes altered in mutSOD1 mice muscles. MutSOD1 up-regulates MyoD, myogenin, atrogin-1 TGFb1, and components of cell response to proteotoxicity (HspB8, Bag1, Bag3). Similar changes occur in cultured ALS myoblasts. Thus, we compared the potential mutSOD1 toxicity in motoneuron (NSC34) and muscle (C2C12) cells. We found that muscle ALS models possess much higher chimotryptic proteasome activity, and autophagy power than motorneuron ALS models. The molecular mutSOD1 behaviour is also very different, since mutSOD1 clearance is much higher in muscle than motoneurons. MutSOD1 forms aggregates and impairs proteasome only in motoneurons, which are more sensitive to superoxide-induced oxidative stress. In muscle cells, mutSOD1 remains soluble even after proteasome inhibition, because of high mutSOD1 autophagic clearance. Therefore, muscle cells efficiently manage misfolded mutSOD1, and its toxicity in muscle may not directly depend on aggregation. Italian Ministry of Health (Conv Mondino/UNIMI); Università di Milano; Regione Lombardia; Fondation Thierry Latran, France; AFM-France.