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


CONCLUSIONS
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.
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Angela M
AM
Jablonski
Department of Pediatrics and Cell Biology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.
Todd
T
Lamitina
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Department of Medicine, University of Washington, Seattle, Washington 98195.
Nicole F
NF
Liachko
Department of Genetics, Erasmus Medical Centre, Cancer Genomics Institute, Rotterdam 3015 CN, The Netherlands.
Mariangela
http://orcid.org/0000-0002-9177-4946
M
Sabatella
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and.
Jiayin
J
Lu
Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Lei
L
Zhang
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Lyle W
LW
Ostrow
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Preetika
P
Gupta
Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Chia-Yen
CY
Wu
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Shachee
S
Doshi
Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
Jelena
J
Mojsilovic-Petrovic
Department of Genetics, Erasmus Medical Centre, Cancer Genomics Institute, Rotterdam 3015 CN, The Netherlands.
Hannes
http://orcid.org/0000-0003-4417-5358
H
Lans
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and.
Jiou
http://orcid.org/0000-0001-9115-8708
J
Wang
Department of Genetics, Erasmus Medical Centre, Cancer Genomics Institute, Rotterdam 3015 CN, The Netherlands.
Brian
B
Kraemer
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.
Robert G
RG
Kalb
D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D016472:Motor Neuron Disease / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D038761:Photobleaching; D034622:RNA Interference / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C547473:Rad-23 protein, C elegans; D049452:Green Fluorescent Proteins
ALS; RAD-23; aging; motor neuron disease; neurodegeneration; proteotoxicity