Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/ijms23084076
Keywords
DNAJC7; amyotrophic lateral sclerosis; molecular chaperones; J proteins; protein misfolding; Hsp70; Hsp90
Funding
- ALS Canada/Brain Canada Project
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Protein misfolding is a common basis for neurodegenerative diseases like ALS. Cellular protein quality control can prevent misfolding, but stressors like reactive oxygen species, genetic mutations, and aging can lead to misfolding. DnaJC7, a molecular chaperone, can prevent misfolding and deal with misfolded proteins through degradation systems or autophagy. Pathogenic variants in the DnaJC7 gene contribute to ALS, but the underlying molecular pathophysiology and function of DnaJC7 remain largely unknown.
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.
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