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

Abstract

Genetic diversity provides a rich repository for understanding the role of proteostasis in the management of the protein fold in human biology. Failure in proteostasis can trigger multiple disease states, affecting both human health and lifespan. Niemann-Pick C1 (NPC1) disease is a rare genetic disorder triggered by mutations in NPC1, a multi-spanning transmembrane protein that is trafficked through the exocytic pathway to late endosomes (LE) and lysosomes (Ly) (LE/Ly) to globally manage cholesterol homeostasis. Defects triggered by >300 NPC1 variants found in the human population inhibit export of NPC1 protein from the endoplasmic reticulum (ER) and/or function in downstream LE/Ly, leading to cholesterol accumulation and onset of neurodegeneration in childhood. We now show that the allosteric inhibitor JG98, that targets the cytosolic Hsp70 chaperone/co-chaperone complex, can significantly improve the trafficking and post-ER protein level of diverse NPC1 variants. Using a new approach to model genetic diversity in human disease, referred to as variation spatial profiling, we show quantitatively how JG98 alters the Hsp70 chaperone/co-chaperone system to adjust the spatial covariance (SCV) tolerance and set-points on an amino acid residue-by-residue basis in NPC1 to differentially regulate variant trafficking, stability, and cholesterol homeostasis, results consistent with the role of BCL2-associated athanogene family co-chaperones in managing the folding status of NPC1 variants. We propose that targeting the cytosolic Hsp70 system by allosteric regulation of its chaperone/co-chaperone based client relationships can be used to adjust the SCV tolerance of proteostasis buffering capacity to provide an approach to mitigate systemic and neurological disease in the NPC1 population.

Isolated Neutropenia/Benign Ethnic Neutropenia: A Common Clinical and Laboratory Finding in Southern and Western Saudi Arabia

“…It is not associated with increased risks of infections. 31 Previous studies have indicated the chronicity of the condition, and follow-up usually indicates the stability and benign nature of the condition. 32 Clinical history can also suggest the presence of other causes of neutropenia.…”

High‐content imaging and structure‐based predictions reveal functional differences between Niemann‐Pick C1 variants

“…A cloned cDNA construct of NPC1, named NPC1 WT‐V that has been used as wild‐type NPC1 in publications by us and others, also contains four variants in comparison to the Genbank reference sequence . These variants are 387 T>C (Y129Y), 1415 T>C (L472P), 1925 T>C (M642T) and 2587 T>C (S863P).…”

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

“…A recent study examined the effects of modulating the HSP70 chaperone/co-chaperone complex on a large number of NPC1 variants (14). That study focused on the effects of an allosteric inhibitor, JG98, that alters the interactions of HSP70 with co-chaperones, especially the BAG family of co-chaperones (73,74).…”

“…Boosting chaperone activity has been proposed as a method to correct the defect in NPC1 mutant cells (12,(24)(25)(26). Changes in molecular chaperone activity are one of the many consequences of HDACi treatment (14,27,28). A quantitative proteomic analysis of the response to HDACi in NPC1 human fibroblasts revealed that the expression of proteins associated with protein folding was modulated (29).…”