Proteasome inhibition alleviates SNARE-dependent neurodegeneration.
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.
Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-5453, USA. sharma11@standford.edu
Manu
M
Sharma
Jacqueline
J
Burré
Thomas C
TC
Südhof
D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D050956:HSP40 Heat-Shock Proteins / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D050600:SNARE Proteins / Q000378:metabolism*
D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D061988:Proteasome Inhibitors; D050600:SNARE Proteins; C088460:cysteine string protein; D046988:Proteasome Endopeptidase Complex