RT Journal Article
SR Electronic
T1 Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14286
OP 14306
DO 10.1523/JNEUROSCI.0642-15.2015
VO 35
IS 42
A1 Jablonski, Angela M.
A1 Lamitina, Todd
A1 Liachko, Nicole F.
A1 Sabatella, Mariangela
A1 Lu, Jiayin
A1 Zhang, Lei
A1 Ostrow, Lyle W.
A1 Gupta, Preetika
A1 Wu, Chia-Yen
A1 Doshi, Shachee
A1 Mojsilovic-Petrovic, Jelena
A1 Lans, Hannes
A1 Wang, Jiou
A1 Kraemer, Brian
A1 Kalb, Robert G.
YR 2015
UL http://www.jneurosci.org/content/35/42/14286.abstract
AB 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.SIGNIFICANCE STATEMENT 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.