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DnaJC7 in Amyotrophic Lateral Sclerosis
Authors:Allison A Dilliott  Catherine M Andary  Meaghan Stoltz  Andrey A Petropavlovskiy  Sali M K Farhan  Martin L Duennwald
Affiliation:1.Department of Neurology and Neurosurgery, McGill University, Montréal, QC H4A 3J1, Canada; (A.A.D.); (S.M.K.F.);2.Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A5C1, Canada; (C.M.A.); (M.S.); (A.A.P.);3.Department of Human Genetics, McGill University, Montréal, QC H4A 3J1, Canada
Abstract:Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin–proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones’ machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in DNAJC7 contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS.
Keywords:DNAJC7  amyotrophic lateral sclerosis  molecular chaperones  J proteins  protein misfolding  Hsp70  Hsp90
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