Premium
Up‐Regulation of Protein Chaperones Preserves Viability of Cells Expressing Toxic Cu/Zn‐Superoxide Dismutase Mutants Associated with Amyotrophic Lateral Sclerosis
Author(s) -
Bruening Wendy,
Roy Josée,
Giasson Benoit,
Figlewicz Denise A,
Mushynski Walter E,
Durham Heather D
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720693.x
Subject(s) - amyotrophic lateral sclerosis , protein aggregation , heat shock protein , superoxide dismutase , mutant , chaperone (clinical) , microbiology and biotechnology , biology , mutant protein , neurodegeneration , biochemistry , chemistry , oxidative stress , gene , pathology , medicine , disease
: Mutations in the Cu/Zn‐superoxidedismutase (SOD‐1) gene underlie some familial cases of amytotrophic lateral sclerosis, a neurodegenerative disorder charactreized by loss of cortical, brainstem, and spinal motor nrurons. 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 (NOH 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 SOG‐1 and prolonged their survival. We propose that insufficiency of molecular chaperones may be directly involved in loss of motor neurons in this disease.