1. Proteasome inhibition alleviates SNARE-dependent neurodegeneration.
- Author
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Sharma M, Burré J, and Südhof TC
- Subjects
- Alzheimer Disease pathology, Animals, Brain drug effects, Brain metabolism, Brain pathology, Cells, Cultured, HSP40 Heat-Shock Proteins deficiency, HSP40 Heat-Shock Proteins metabolism, Humans, Membrane Proteins deficiency, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Neurons drug effects, Neurons metabolism, Parkinson Disease pathology, Phenotype, Nerve Degeneration metabolism, Nerve Degeneration pathology, Proteasome Endopeptidase Complex metabolism, Proteasome Inhibitors pharmacology, SNARE Proteins metabolism
- Abstract
Activation of the proteasomal degradation of misfolded proteins has been proposed as a therapeutic strategy for treating neurodegenerative diseases, but it is unclear whether proteasome dysfunction contributes to neurodegeneration. We tested the role of proteasome activity in neurodegeneration developed by mice lacking cysteine string protein-α (CSPα). Unexpectedly, we found that proteasome inhibitors alleviated neurodegeneration in CSPα-deficient mice, reversing impairment of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-complex assembly and extending life span. We tested whether dysfunctional SNARE-complex assembly could contribute to neurodegeneration in Alzheimer's and Parkinson's disease by analyzing postmortem brain tissue from these patients; we found reduced SNARE-complex assembly in the brain tissue samples. Our results suggest that proteasomal activation may not always be beneficial for alleviating neurodegeneration and that blocking the proteasome may represent a potential therapeutic avenue for treating some forms of neurodegenerative disease.
- Published
- 2012
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