Individualized management of genetic diversity in Niemann-Pick C1 through modulation of the Hsp70 chaperone system

Genetic diversity offers a wealth of insights into how proteostasis—the process that ensures proper protein folding and function—is managed in human biology. When this system fails, it can trigger a variety of disease states, ultimately impacting human health and lifespan. One striking example is Niemann-Pick C1 (NPC1) disease, a rare genetic disorder caused by mutations in NPC1, a multi-spanning transmembrane protein that normally traffics through the exocytic pathway to late endosomes and lysosomes to regulate cholesterol homeostasis.

More than 300 variants of NPC1 have been identified in the human population, and many of these mutations impair the export of NPC1 from the endoplasmic reticulum or its function in downstream late endosomes and lysosomes. These defects lead to the accumulation of cholesterol and are associated with the early onset of neurodegeneration during childhood. In our study, we demonstrate that the allosteric inhibitor JG98, which targets the cytosolic Hsp70 chaperone/co-chaperone complex, can markedly improve the trafficking and post-endoplasmic reticulum protein levels of a wide range of NPC1 variants.

We employed a novel approach termed variation spatial profiling to quantitatively assess how JG98 modifies the Hsp70 chaperone/co-chaperone system. This technique allowed us to evaluate changes in spatial covariance tolerance and set-points on an amino acid residue-by-residue basis in NPC1. Our findings indicate that JG98 differentially regulates the trafficking, stability, and overall cholesterol homeostasis of NPC1 variants, consistent with the known roles of BCL2-associated athanogene family co-chaperones in managing protein folding.

Overall, our results suggest that targeting the cytosolic Hsp70 system through allosteric regulation of its client relationships can effectively adjust the spatial covariance tolerance of the proteostasis buffering capacity. This strategy holds promise as a novel therapeutic approach for mitigating both systemic and neurological disease in individuals affected by NPC1 mutations.