Characterization and Hsp104-induced artificial clearance of familial ALS-related SOD1 aggregates.
Hsp104, a molecular chaperone protein, originates from Saccharomyces cerevisiae and shows potential for development as a therapeutic disaggregase for the treatment of neurodegenerative disorders. This study shows that aggregates of mutant superoxide dismutase 1 (SOD1), which cause amyotrophic lateral sclerosis (ALS), are disaggregated by Hsp104 in an ATP-dependent manner. Mutant SOD1 aggregates were first characterized using fluorescence loss in photobleaching experiments based on the reduced mobility of aggregated proteins. Hsp104 restored the mobility of mutant SOD1 proteins to a level comparable with that of the wild-type. However, ATPase-deficient Hsp104 mutants did not restore mobility, suggesting that, rather than preventing aggregation, Hsp104 disaggregates mutant SOD1 after it has aggregated. Despite the restored mobility, however, mutant SOD1 proteins existed as trimers or other higher-order structures, rather than as naturally occurring dimers. This study sheds further light on the mechanisms underlying the disaggregation of SOD1 mutant aggregates in ALS.
Pubmed ID: 23583391 RIS Download
Adenosine Triphosphate | Amyotrophic Lateral Sclerosis | Animals | Fluorescence Resonance Energy Transfer | Heat-Shock Proteins | Humans | Hydrolysis | Mice | Mutant Proteins | Saccharomyces cerevisiae Proteins | Superoxide Dismutase | Superoxide Dismutase-1