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.

, , , , ,
doi.org/10.1523/JNEUROSCI.0642-15.2015, hdl.handle.net/1765/83743
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