Research ArticleNeurodegenerative Disease

Proteasome Inhibition Alleviates SNARE-Dependent Neurodegeneration

See allHide authors and affiliations

Science Translational Medicine  15 Aug 2012:
Vol. 4, Issue 147, pp. 147ra113
DOI: 10.1126/scitranslmed.3004028

You are currently viewing the abstract.

View Full Text


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.

View Full Text