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 Sep 28
ISSN2041-1723
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.

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) /
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