Proteasome inhibition enhances the stability of mouse [formula omitted] superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis

• Published in: Journal of the neurological sciences Vol. 139; no. 1; pp. 15 - 20
• Main Authors: Hoffman, Eric K., Wilcox, Heide M., Scott, Richard W., Siman, Robert
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 1996
• Subjects: [formula omitted] superoxide dismutase; Amyotrophic lateral sclerosis; Proteasome; Proteasome inhibitor; Proteolytic degradation; SOD1 mutations; FALS; Proteasome inhibitor; SOD1 mutations; Cu Zn SOD; Amyotrophic lateral sclerosis; Proteolytic degradation; Cu Zn superoxide dismutase; Proteasome
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/0022-510X(96)00031-7

Point mutations occurring within the Cu Zn superoxide dismutase ( SOD1) gene have been implicated in the etiology of some cases of familial amyotrophic lateral sclerosis (FALS). In order to better understand the functional consequences of these mutations, we have introduced FALS mutations into the mouse SOD1 gene and studied the expression of the mutant templates in stably transformed cell lines. Pulse-chase analyses of lysates derived from cell lines stably expressing the Cu Zn SOD isoforms indicate that the FALS mutant Cu Zn SOD proteins are turned over more rapidly than wild-type SOD. Protease inhibitors specific for the major intracellular proteolytic activities were used to characterize the degradative pathways involved in the turnover of mutant Cu Zn SOD. Inhibition of the chymotrypsin-like activity of the proteasome (also known as multicatalytic proteinase or ubiquitin, ATP-dependent proteinase) by a synthetic dipeptide aldehyde led to a significant increase in levels of the mutant Cu Zn SOD implicating this proteolytic pathway in the turnover of the FALS mutant SOD proteins.