Abstract
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.
Original language | English (US) |
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Pages (from-to) | 14286-14306 |
Number of pages | 21 |
Journal | Journal of Neuroscience |
Volume | 35 |
Issue number | 42 |
DOIs | |
State | Published - Oct 21 2015 |
Keywords
- ALS
- Aging
- Motor neuron disease
- Neurodegeneration
- Proteotoxicity
- RAD-23
ASJC Scopus subject areas
- General Neuroscience