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Over 100 mutants in superoxide dismutase 1 (SOD1) are reported in familial amyotrophic lateral sclerosis (ALS). However, the precise mechanism by which they are degraded through a ubiquitin‐proteasomal pathway (UPP) remains unclear. Here, we report that heat‐shock protein (Hsp) or heat‐shock cognate (Hsc)70, and the carboxyl terminus of the Hsc70‐interacting protein (CHIP), are involved in proteasomal degradation of mutant SOD1. Only mutant SOD1 interacted with Hsp/Hsc70 in vivo, and in vitro experiments revealed that Hsp/Hsc70 preferentially interacted with apo‐SOD1 or dithiothreitol (DTT)‐treated holo‐SOD1, compared with metallated or oxidized forms. CHIP, a binding partner of Hsp/Hsc70, interacted only with mutant SOD1 and promoted its degradation. Both Hsp70 and CHIP promoted polyubiquitination of mutant SOD1‐associated molecules, but not of mutant SOD1, indicating that mutant …