Inhibition of chaperone activity is a shared property of several Cu,Zn-superoxide dismutase mutants that cause amyotrophic lateral sclerosis
Authors
Tummala, HemachandJung, Chelowha
Tiwari, Ashutosh
Higgins, Cynthia M. J.
Hayward, Lawrence J.
Xu, Zuoshang
UMass Chan Affiliations
Department of Molecular Genetics and MicrobiologyDepartment of Neurology
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2005-03-09Keywords
Amyotrophic Lateral SclerosisAnimals
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molecular Chaperones
*Mutation
Spinal Cord
Superoxide Dismutase
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration, paralysis, and death. Mutant Cu,Zn-superoxide dismutase (SOD1) causes a subset of ALS by an unidentified toxic property. Increasing evidence suggests that chaperone dysfunction plays a role in motor neuron degeneration in ALS. To investigate the relationship between mutant SOD1 expression and chaperone dysfunction, we measured chaperone function in central nervous system tissue lysates from normal mice and transgenic mice expressing human SOD1 variants. We observed a significant decrease in chaperone activity in tissues from mice expressing ALS-linked mutant SOD1 but not control mice expressing human wild type SOD1. This decrease was detected only in the spinal cord, became apparent by 60 days of age (before the onset of muscle weakness and significant motor neuron loss), and persisted throughout the late stages. In addition, this impairment of chaperone activity occurred only in cytosolic but not in mitochondrial and nuclear fractions. Furthermore, multiple recombinant human SOD1 mutants with differing biochemical and biophysical properties inhibited chaperone function in a cell-free extract of normal mouse spinal cords. Thus, mutant SOD1 proteins may impair chaperone function independent of gene expression in vivo, and this inhibition may be a shared property of ALS-linked mutant SOD1 proteins.Source
J Biol Chem. 2005 May 6;280(18):17725-31. Epub 2005 Mar 7. Link to article on publisher's siteDOI
10.1074/jbc.M501705200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42334PubMed ID
15753080Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M501705200