Title | Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Guiberson NGuy Lewis, Pineda A, Abramov D, Kharel P, Carnazza KE, Wragg RT, Dittman JS, Burré J |
Journal | Nat Commun |
Volume | 9 |
Issue | 1 |
Pagination | 3986 |
Date Published | 2018 Sep 28 |
ISSN | 2041-1723 |
Abstract | Heterozygous de novo mutations in the neuronal protein Munc18-1 are linked to epilepsies, intellectual disability, movement disorders, and neurodegeneration. These devastating diseases have a poor prognosis and no known cure, due to lack of understanding of the underlying disease mechanism. To determine how mutations in Munc18-1 cause disease, we use newly generated S. cerevisiae strains, C. elegans models, and conditional Munc18-1 knockout mouse neurons expressing wild-type or mutant Munc18-1, as well as in vitro studies. We find that at least five disease-linked missense mutations of Munc18-1 result in destabilization and aggregation of the mutant protein. Aggregates of mutant Munc18-1 incorporate wild-type Munc18-1, depleting functional Munc18-1 levels beyond hemizygous levels. We demonstrate that the three chemical chaperones 4-phenylbutyrate, sorbitol, and trehalose reverse the deficits caused by mutations in Munc18-1 in vitro and in vivo in multiple models, offering a novel strategy for the treatment of varied encephalopathies. |
DOI | 10.1038/s41467-018-06507-4 |
Alternate Journal | Nat Commun |
PubMed ID | 30266908 |
PubMed Central ID | PMC6162227 |
Grant List | R01-GM095674 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) / R01 GM095674 / GM / NIGMS NIH HHS / United States T32GM007739 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) / R01 NS102181 / NS / NINDS NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |