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Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance
- Source :
- Journal of Neuroscience, 35(42), 14286-14306. Society for Neuroscience
- Publication Year :
- 2015
- Publisher :
- Society for Neuroscience, 2015.
-
Abstract
- 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 ofCaenorhabditis elegansengineered 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 STATEMENTIn 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.
- Subjects :
- Male
Genotype
SOD1
Green Fluorescent Proteins
Biology
Motor Activity
DNA-binding protein
Neuroprotection
Animals, Genetically Modified
Rats, Sprague-Dawley
Mice
Ubiquitin
Mutant protein
medicine
Animals
Humans
Motor Neuron Disease
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Cells, Cultured
Photobleaching
General Neuroscience
Neurodegeneration
Articles
Motor neuron
medicine.disease
Cell biology
Rats
DNA-Binding Proteins
Disease Models, Animal
medicine.anatomical_structure
Proteotoxicity
Biochemistry
Animals, Newborn
Gene Expression Regulation
Mutation
biology.protein
RNA Interference
Subjects
Details
- Language :
- English
- ISSN :
- 02706474
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroscience, 35(42), 14286-14306. Society for Neuroscience
- Accession number :
- edsair.doi.dedup.....772c9916302192bc27e5a65a229adfa0