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J Neurosci. 2015 Oct 21;35(42):14286-306. doi: 10.1523/JNEUROSCI.0642-15.2015.

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

Author information

1
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
2
Department of Pediatrics and Cell Biology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.
3
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Department of Medicine, University of Washington, Seattle, Washington 98195.
4
Department of Genetics, Erasmus Medical Centre, Cancer Genomics Institute, Rotterdam 3015 CN, The Netherlands.
5
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and.
6
Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
7
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
8
Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, kalb@email.chop.edu.

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 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.

KEYWORDS:

ALS; RAD-23; aging; motor neuron disease; neurodegeneration; proteotoxicity

PMID:
26490867
PMCID:
PMC4683688
DOI:
10.1523/JNEUROSCI.0642-15.2015
[Indexed for MEDLINE]
Free PMC Article

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