DNAJC7, a Molecular Chaperone Protein that Modulates Protein Misfolding in Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease associated with protein misfolding and dysregulated cellular protein quality control mechanisms. Molecular chaperones, and heat shock proteins (Hsp), are key players in maintaining cellular protein quality control. DNAJC7 is an understudied cytosolic Hsp40 that works together with Hsp70 and Hsp90 to regulate proper protein folding or degradation. Of note, mutations in the gene encoding DNAJC7 were discovered to cause familial ALS. We asked whether ALS-associated mutations in DNAJC7 compromise its function as a chaperone, which may cause the toxic accumulation of misfolded proteins. This study attempts to uncover the functions of DNAJC7 in folding ALS-associated proteins, TDP-43 and FUS, using a yeast model, mammalian cultured cells, and human pathological tissue. Furthermore, we engineered DNAJC7 mutations to be used in future studies. We propose that DNAJC7 may be involved in the proper folding of TDP-43 and FUS by allowing these proteins to be passed from Hsp90 to Hsp70 and thus prevent their misfolding and the ensuing toxicity