PT  - JOURNAL ARTICLE
AU  - Angela M. Jablonski
AU  - Todd Lamitina
AU  - Nicole F. Liachko
AU  - Mariangela Sabatella
AU  - Jiayin Lu
AU  - Lei Zhang
AU  - Lyle W. Ostrow
AU  - Preetika Gupta
AU  - Chia-Yen Wu
AU  - Shachee Doshi
AU  - Jelena Mojsilovic-Petrovic
AU  - Hannes Lans
AU  - Jiou Wang
AU  - Brian Kraemer
AU  - Robert G. Kalb
TI  - Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance
AID  - 10.1523/JNEUROSCI.0642-15.2015
DP  - 2015 Oct 21
TA  - The Journal of Neuroscience
PG  - 14286--14306
VI  - 35
IP  - 42
4099  - http://www.jneurosci.org/content/35/42/14286.short
4100  - http://www.jneurosci.org/content/35/42/14286.full
SO  - J. Neurosci.2015 Oct 21; 35
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.