Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones.
| Publication Type | Academic Article |
| Authors | Guiberson N, Pineda A, Abramov D, Kharel P, Carnazza K, Wragg R, Dittman J, Burré J |
| Journal | Nat Commun |
| Volume | 9 |
| Issue | 1 |
| Pagination | 3986 |
| Date Published | 09/28/2018 |
| ISSN | 2041-1723 |
| Keywords | Brain Diseases, Munc18 Proteins, Mutation, Missense, Organic Chemicals |
| 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 |
| PubMed ID | 30266908 |
| PubMed Central ID | PMC6162227 |