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

Noah Guy Lewis Guiberson, André Pineda, Debra Abramov, Parinati Kharel, Kathryn E. Carnazza, Rachel T. Wragg, Jeremy S. Dittman and Jacqueline Burré ()
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Noah Guy Lewis Guiberson: Brain and Mind Research Institute & Appel Institute for Alzheimer’s Disease Research, Weill Cornell Medicine
André Pineda: Brain and Mind Research Institute & Appel Institute for Alzheimer’s Disease Research, Weill Cornell Medicine
Debra Abramov: Brain and Mind Research Institute & Appel Institute for Alzheimer’s Disease Research, Weill Cornell Medicine
Parinati Kharel: Brain and Mind Research Institute & Appel Institute for Alzheimer’s Disease Research, Weill Cornell Medicine
Kathryn E. Carnazza: Brain and Mind Research Institute & Appel Institute for Alzheimer’s Disease Research, Weill Cornell Medicine
Rachel T. Wragg: Weill Cornell Medicine
Jeremy S. Dittman: Weill Cornell Medicine
Jacqueline Burré: Brain and Mind Research Institute & Appel Institute for Alzheimer’s Disease Research, Weill Cornell Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-18

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.

Date: 2018
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DOI: 10.1038/s41467-018-06507-4

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