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- W2892851649 abstract "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." @default.
- W2892851649 created "2018-10-05" @default.
- W2892851649 creator A5002969639 @default.
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- W2892851649 date "2018-09-28" @default.
- W2892851649 modified "2023-10-13" @default.
- W2892851649 title "Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones" @default.
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- W2892851649 doi "https://doi.org/10.1038/s41467-018-06507-4" @default.
- W2892851649 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6162227" @default.
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- W2892851649 hasPublicationYear "2018" @default.
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