Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance

Angela M. Jablonski, Todd Lamitina, Nicole F. Liachko, Mariangela Sabatella, Jiayin Lu, Lei Zhang, Lyle W. Ostrow, Preetika Gupta, Chia Yen Wu, Shachee Doshi, Jelena Mojsilovic-Petrovic, Hannes Lans, Jiou Wang, Brian Kraemer, Robert G. Kalb

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)14286-14306
Number of pages21
JournalJournal of Neuroscience
Volume35
Issue number42
DOIs
StatePublished - Oct 21 2015

Keywords

  • ALS
  • Aging
  • Motor neuron disease
  • Neurodegeneration
  • Proteotoxicity
  • RAD-23

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Jablonski, A. M., Lamitina, T., Liachko, N. F., Sabatella, M., Lu, J., Zhang, L., Ostrow, L. W., Gupta, P., Wu, C. Y., Doshi, S., Mojsilovic-Petrovic, J., Lans, H., Wang, J., Kraemer, B., & Kalb, R. G. (2015). Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance. Journal of Neuroscience, 35(42), 14286-14306. https://doi.org/10.1523/JNEUROSCI.0642-15.2015