Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones. Academic Article uri icon

Overview

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.

publication date

  • September 28, 2018

Research

keywords

  • Brain Diseases
  • Munc18 Proteins
  • Mutation, Missense
  • Organic Chemicals

Identity

PubMed Central ID

  • PMC6162227

Scopus Document Identifier

  • 85054079785

Digital Object Identifier (DOI)

  • 10.3389/fncom.2013.00193

PubMed ID

  • 30266908

Additional Document Info

volume

  • 9

issue

  • 1