Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance

• Published in: The Journal of neuroscience Vol. 35; no. 42; pp. 14286 - 14306
• Main Authors: Jablonski, Angela M, Lamitina, Todd, Liachko, Nicole F, Sabatella, Mariangela, Lu, Jiayin, Zhang, Lei, Ostrow, Lyle W, Gupta, Preetika, Wu, Chia-Yen, Doshi, Shachee, Mojsilovic-Petrovic, Jelena, Lans, Hannes, Wang, Jiou, Kraemer, Brian, Kalb, Robert G
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 21.10.2015
• Subjects: Animals; Animals, Genetically Modified; Animals, Newborn; Caenorhabditis elegans; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cells, Cultured; Disease Models, Animal; DNA-Binding Proteins - metabolism; Gene Expression Regulation - genetics; Genotype; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Male; Mice; Motor Activity - genetics; Motor Neuron Disease - genetics; Mutation - genetics; Photobleaching; Rats; Rats, Sprague-Dawley; RNA Interference - physiology; ALS; neurodegeneration; RAD-23; motor neuron disease; aging; proteotoxicity
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0642-15.2015

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. 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.