Up‐Regulation of Protein Chaperones Preserves Viability of Cells Expressing Toxic Cu/Zn‐Superoxide Dismutase Mutants Associated with Amyotrophic Lateral Sclerosis

作者：Wendy Bruening, Josée Roy, Benoit I. Giasson, Denise A. Figlewicz, Walter E. Mushynski, Heather D. Durham · 发表于：Journal of Neurochemistry · 年份：1999 · DOI：10.1046/j.1471-4159.1999.0720693.x · 被引用次数：260 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neurogenetic and Muscular Disorders Research、Neurological diseases and metabolism

Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene underlie some familial cases of amyotrophic lateral sclerosis, a neurodegenerative disorder characterized by loss of cortical, brainstem, and spinal motor neurons. We present evidence that SOD-1 mutants alter the activity of molecular chaperones that aid in proper protein folding and targeting of abnormal proteins for degradation. In a cultured cell line (NIH 3T3), resistance to mutant SOD-1 toxicity correlated with increased overall chaperoning activity (measured by the ability of cytosolic extracts to prevent heat denaturation of catalase) as well as with up-regulation of individual chaperones/stress proteins. In transgenic mice expressing human SOD-1 with the G93A mutation, chaperoning activity was decreased in lumbar spinal cord but increased or unchanged in clinically unaffected tissues. Increasing the level of the stress-inducible chaperone 70-kDa heat shock protein by gene transfer reduced formation of mutant SOD-containing proteinaceous aggregates in cultured primary motor neurons expressing G93A SOD-1 and prolonged their survival. We propose that insufficiency of molecular chaperones may be directly involved in loss of motor neurons in this disease.