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


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.

SUBMITTER: Guiberson NGL 

PROVIDER: S-EPMC6162227 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Guiberson Noah Guy Lewis NGL   Pineda André A   Abramov Debra D   Kharel Parinati P   Carnazza Kathryn E KE   Wragg Rachel T RT   Dittman Jeremy S JS   Burré Jacqueline J  

Nature communications 20180928 1


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,  ...[more]

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