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

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.

• Authors: 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
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 42 Pg. 14286-306 (Oct 21 2015) ISSN: 1529-2401 [Electronic] United States
• PMID: 26490867 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the authors 0270-6474/15/3514286-21$15.00/0.

Chemical References

• Caenorhabditis elegans Proteins
• DNA-Binding Proteins
• Rad-23 protein, C elegans
• Green Fluorescent Proteins

Topics

• Animals
• Animals, Genetically Modified
• Animals, Newborn
• Caenorhabditis elegans
• Caenorhabditis elegans Proteins (genetics, metabolism)
• Cells, Cultured
• DNA-Binding Proteins (metabolism)
• Disease Models, Animal
• Gene Expression Regulation (genetics)
• Genotype
• Green Fluorescent Proteins (genetics, metabolism)
• Humans
• Male
• Mice
• Motor Activity (genetics)
• Motor Neuron Disease (genetics)
• Mutation (genetics)
• Photobleaching
• RNA Interference (physiology)
• Rats
• Rats, Sprague-Dawley