Research ArticleNeurodegenerative Disease

Proteasome Inhibition Alleviates SNARE-Dependent Neurodegeneration

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

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Ensnaring Neurodegeneration

Many believe that a decrease in proteasome activity contributes to the pathogenesis of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Thus, activation of proteasome activity has been considered a promising therapeutic strategy for treating neurodegenerative diseases. In a new study, Sharma et al. tested proteasome inhibitors in mice with neurodegeneration caused by deletion of cysteine string protein-α. Mice lacking cysteine string protein-α die early because of loss of synapses and neuronal death, which results from loss of the SNARE protein SNAP-25 (for which cysteine string protein-α is a chaperone), and a decrease in the assembly of SNARE complexes. Surprisingly, the authors found the opposite of what they expected: Instead of accelerating neurodegeneration, proteasome inhibitors alleviated neurodegeneration. This unexpected result demonstrates that at least for this form of neurodegeneration, proteasome inhibition does not represent a pathogenic mechanism, but instead can be used as a therapeutic strategy. The researchers showed that the proteasome inhibitors alleviated neurodegeneration by increasing SNAP-25 concentrations and enhancing SNARE-complex assembly. They then demonstrated that SNARE-complex assembly is impaired in human brain tissue from patients with neurodegenerative diseases. The impact of this study may go beyond neurodegeneration because systemic administration of proteasome inhibitors is currently being tested as a cancer treatment. Proteasome inhibitors also may help in the treatment of other diseases such as cystic fibrosis and nephrogenic diabetes insipidus, which are caused by proteasomal degradation of functionally important proteins.