Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance
The Journal of Neuroscience , Volume 35 - Issue 42 p. 14286- 14306
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.
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|The Journal of Neuroscience
|Department of Molecular Genetics
Jablonski, A. M., Lamitina, T., Liachko, N. F., Sabatella, M., Lu, J., Zhang, L., … Kalb, R. G. (2015). Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance. The Journal of Neuroscience, 35(42), 14286–14306. doi:10.1523/JNEUROSCI.0642-15.2015