Myopathy mutations in DNAJB6 slow conformer specific substrate processing that is corrected by NEF modulation

Abstract

Molecular chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. As such, mutations or deficiencies within the chaperone network can lead to disease. In fact, dominant mutations in DNAJB6 (Hsp40/Sis1), an Hsp70 co-chaperone, leads to a protein aggregate myopathy termed Limb-Girdle Muscular Dystrophy Type D1 (LGMDD1). DNAJB6 client proteins and co-chaperone interactions in skeletal muscle are not known. Here, we used the yeast prion model client in conjunction with in vitro chaperone activity assays to gain mechanistic insights, and found that LGMDD1 mutants affect Hsp40 functions. Strikingly, the mutants changed the structure of client protein aggregates, as determined by altered distribution of prion strains. They also impair the Hsp70 ATPase cycle, dimerization, and substrate processing and consequently poison the function of wild-type protein. These results define the mechanisms by which LGMDD1 mutations alter chaperone activity and provide avenues for therapeutic intervention.

DNAJB6 Isoform Specific Knockdown: Therapeutic Potential for LGMDD1

“…Additionally, there is mixed evidence whether disease pathogenesis occurs via a dominant negative effect, a toxic gain of function, or possibly a combination of both. 4,5,[7][8][9][10][11] Although gene knockdown is a common approach for treating dominantly inherited disorders, this approach may be deleterious in LGMDD1 based on DNAJB6 knockout data in cells and mice. However, haploinsufficiency may be tolerated, as heterozygous knockout mice have no reported phenotype, and human mutation databases such as gnomAD, contain frameshift and nonsense mutations scattered throughout DNAJB6 in presumably healthy patients.…”