Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance
Misfolded proteins accumulate and aggregate in neurodegenerative disease. The existence of these deposits reflects a derangement in the protein homeostasis machinery. Using a candidate gene screen, we report that loss of RAD-23 protects against the toxicity of proteins known to aggregate in amyotrop...
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Published in | The Journal of neuroscience Vol. 35; no. 42; pp. 14286 - 14306 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
21.10.2015
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Subjects | |
Online Access | Get full text |
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Summary: | Misfolded proteins accumulate and aggregate in neurodegenerative disease. The existence of these deposits reflects a derangement in the protein homeostasis machinery. Using a candidate gene screen, we report that loss of RAD-23 protects against the toxicity of proteins known to aggregate in amyotrophic lateral sclerosis. Loss of RAD-23 suppresses the locomotor deficit of Caenorhabditis elegans engineered to express mutTDP-43 or mutSOD1 and also protects against aging and proteotoxic insults. Knockdown of RAD-23 is further neuroprotective against the toxicity of SOD1 and TDP-43 expression in mammalian neurons. Biochemical investigation indicates that RAD-23 modifies mutTDP-43 and mutSOD1 abundance, solubility, and turnover in association with altering the ubiquitination status of these substrates. In human amyotrophic lateral sclerosis spinal cord, we find that RAD-23 abundance is increased and RAD-23 is mislocalized within motor neurons. We propose a novel pathophysiological function for RAD-23 in the stabilization of mutated proteins that cause neurodegeneration.
In this work, we identify RAD-23, a component of the protein homeostasis network and nucleotide excision repair pathway, as a modifier of the toxicity of two disease-causing, misfolding-prone proteins, SOD1 and TDP-43. Reducing the abundance of RAD-23 accelerates the degradation of mutant SOD1 and TDP-43 and reduces the cellular content of the toxic species. The existence of endogenous proteins that act as "anti-chaperones" uncovers new and general targets for therapeutic intervention. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: A.M.J., T.L., N.F.L., M.S., J.L., L.Z., L.W.O., C.-Y.W., H.L., J.W., B.K., and R.G.K. designed research; A.M.J., T.L., N.F.L., M.S., J.L., L.Z., P.G., C.-Y.W., S.D., H.L., J.W., and B.K. performed research; A.M.J., L.W.O., and J.M.-P. contributed unpublished reagents/analytic tools; A.M.J., T.L., N.F.L., M.S., J.L., P.G., C.-Y.W., S.D., H.L., J.W., B.K., and R.G.K. analyzed data; A.M.J. and R.G.K. wrote the paper. |
ISSN: | 0270-6474 1529-2401 |
DOI: | 10.1523/JNEUROSCI.0642-15.2015 |