Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance

Angela M. Jablonski, Todd Lamitina, Nicole F. Liachko, Mariangela Sabatella, Jiayin Lu, Lei Zhang, Lyle W. Ostrow, Preetika Gupta, Chia Yen Wu, Shachee Doshi, Jelena Mojsilovic-Petrovic, Hannes Lans, Jiou Wang, Brian Kraemer, Robert G. Kalb*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)14286-14306
Number of pages21
JournalJournal of Neuroscience
Volume35
Issue number42
DOIs
StatePublished - Oct 21 2015

Fingerprint

Motor Neuron Disease
Mutant Proteins
Amyotrophic Lateral Sclerosis
Proteins
Ubiquitination
Caenorhabditis elegans
Motor Neurons
Neurodegenerative Diseases
Solubility
Spinal Cord
Homeostasis
Neurons
Genes

Keywords

  • ALS
  • Aging
  • Motor neuron disease
  • Neurodegeneration
  • Proteotoxicity
  • RAD-23

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 42. pp. 14286-14306.
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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.",
keywords = "ALS, Aging, Motor neuron disease, Neurodegeneration, Proteotoxicity, RAD-23",
author = "Jablonski, {Angela M.} and Todd Lamitina and Liachko, {Nicole F.} and Mariangela Sabatella and Jiayin Lu and Lei Zhang and Ostrow, {Lyle W.} and Preetika Gupta and Wu, {Chia Yen} and Shachee Doshi and Jelena Mojsilovic-Petrovic and Hannes Lans and Jiou Wang and Brian Kraemer and Kalb, {Robert G.}",
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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 2015, 'Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance', Journal of Neuroscience, vol. 35, no. 42, pp. 14286-14306. https://doi.org/10.1523/JNEUROSCI.0642-15.2015

Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance. / 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.

In: Journal of Neuroscience, Vol. 35, No. 42, 21.10.2015, p. 14286-14306.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of rad-23 protects against models of motor neuron disease by enhancing mutant protein clearance

AU - Jablonski, Angela M.

AU - Lamitina, Todd

AU - Liachko, Nicole F.

AU - Sabatella, Mariangela

AU - Lu, Jiayin

AU - Zhang, Lei

AU - Ostrow, Lyle W.

AU - Gupta, Preetika

AU - Wu, Chia Yen

AU - Doshi, Shachee

AU - Mojsilovic-Petrovic, Jelena

AU - Lans, Hannes

AU - Wang, Jiou

AU - Kraemer, Brian

AU - Kalb, Robert G.

PY - 2015/10/21

Y1 - 2015/10/21

N2 - 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.

AB - 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.

KW - ALS

KW - Aging

KW - Motor neuron disease

KW - Neurodegeneration

KW - Proteotoxicity

KW - RAD-23

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U2 - 10.1523/JNEUROSCI.0642-15.2015

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C2 - 26490867

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