RRC ID 45578
著者 Jablonski AM, Lamitina T, Liachko NF, Sabatella M, Lu J, Zhang L, Ostrow LW, Gupta P, Wu CY, Doshi S, Mojsilovic-Petrovic J, Lans H, Wang J, Kraemer B, Kalb RG.
タイトル Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance.
ジャーナル J Neurosci
Abstract UNLABELLED: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.
巻・号 35(42)
ページ 14286-306
公開日 2015-10-21
DOI 10.1523/JNEUROSCI.0642-15.2015
PII 35/42/14286
PMID 26490867
PMC PMC4683688
MeSH Animals Animals, Genetically Modified Animals, Newborn Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cells, Cultured DNA-Binding Proteins / metabolism Disease Models, Animal 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 RNA Interference / physiology* Rats Rats, Sprague-Dawley
IF 5.674
引用数 11
WOS 分野 NEUROSCIENCES
リソース情報
線虫 tm3690 tm2595 tm2915 tm1380 tm544 tm659 tm3247 tm1574 tm2909 tm2073 tm6057 tm5511 tm1743 tm2839 tm5861 tm794