Individualized management of genetic diversity in Niemann-Pick C1 through modulation of the Hsp70 chaperone system
| Autor: | Chao Wang, William E. Balch, Samantha M. Scott, Jason E. Gestwicki, Pei Zhao, Hao Shao, Darren M. Hutt, Shuhong Sun |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Endosome
Population Endosomes Endoplasmic Reticulum Type C Medical and Health Sciences Article 03 medical and health sciences Cytosol 0302 clinical medicine Allosteric Regulation Niemann-Pick C1 Protein Niemann-Pick Disease hemic and lymphatic diseases Genetics medicine 2.1 Biological and endogenous factors Humans HSP70 Heat-Shock Proteins Aetiology education Molecular Biology Genetics (clinical) 030304 developmental biology Genetics & Heredity 0303 health sciences education.field_of_study biology Endoplasmic reticulum Neurodegeneration Genetic Variation Niemann-Pick Disease Type C General Medicine Biological Sciences medicine.disease Transmembrane protein Cell biology Cholesterol Proteostasis Chaperone (protein) biology.protein NPC1 Lysosomes 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | Hum Mol Genet Human molecular genetics, vol 29, iss 1 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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