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

Nat Commun. 2018 Sep 28;9(1):3986. doi: 10.1038/s41467-018-06507-4.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Diseases / genetics*
  • Brain Diseases / metabolism
  • Brain Diseases / prevention & control
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Mice, Knockout
  • Munc18 Proteins / genetics*
  • Munc18 Proteins / metabolism
  • Mutation, Missense*
  • Neurons / drug effects
  • Neurons / metabolism
  • Organic Chemicals / pharmacology*
  • Phenylbutyrates / pharmacology
  • Protein Aggregates / drug effects
  • Protein Aggregation, Pathological / prevention & control
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sorbitol / pharmacology
  • Trehalose / pharmacology


  • Caenorhabditis elegans Proteins
  • Munc18 Proteins
  • Organic Chemicals
  • Phenylbutyrates
  • Protein Aggregates
  • Saccharomyces cerevisiae Proteins
  • Sorbitol
  • 4-phenylbutyric acid
  • Trehalose