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Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones.

TitleMechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones.
Publication TypeJournal Article
Year of Publication2018
AuthorsGuiberson NGuy Lewis, Pineda A, Abramov D, Kharel P, Carnazza KE, Wragg RT, Dittman JS, Burré J
JournalNat Commun
Volume9
Issue1
Pagination3986
Date Published2018 09 28
ISSN2041-1723
KeywordsAnimals, Brain Diseases, Caenorhabditis elegans Proteins, Cell Line, Tumor, Cells, Cultured, HEK293 Cells, Humans, Mice, Knockout, Munc18 Proteins, Mutation, Missense, Neurons, Organic Chemicals, Phenylbutyrates, Protein Aggregates, Protein Aggregation, Pathological, Saccharomyces cerevisiae Proteins, Sorbitol, Trehalose
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.

DOI10.1038/s41467-018-06507-4
Alternate JournalNat Commun
PubMed ID30266908
PubMed Central IDPMC6162227
Grant ListR01-GM095674 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) / International
R01 GM095674 / GM / NIGMS NIH HHS / United States
T32GM007739 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) / International
R01 NS102181 / NS / NINDS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States