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Targeted stabilization of Munc18-1 function via pharmacological chaperones.

TitleTargeted stabilization of Munc18-1 function via pharmacological chaperones.
Publication TypeJournal Article
Year of Publication2020
AuthorsAbramov D, Guiberson NGuy Lewis, Daab A, Na Y, Petsko GA, Sharma M, Burré J
JournalEMBO Mol Med
Paginatione12354
Date Published2020 Dec 17
ISSN1757-4684
Abstract

Heterozygous de novo mutations in the neuronal protein Munc18-1 cause syndromic neurological symptoms, including severe epilepsy, intellectual disability, developmental delay, ataxia, and tremor. No disease-modifying therapy exists to treat these disorders, and while chemical chaperones have been shown to alleviate neuronal dysfunction caused by missense mutations in Munc18-1, their required high concentrations and potential toxicity necessitate a Munc18-1-targeted therapy. Munc18-1 is essential for neurotransmitter release, and mutations in Munc18-1 have been shown to cause neuronal dysfunction via aggregation and co-aggregation of the wild-type protein, reducing functional Munc18-1 levels well below hemizygous levels. Here, we identify two pharmacological chaperones via structure-based drug design, that bind to wild-type and mutant Munc18-1, and revert Munc18-1 aggregation and neuronal dysfunction in vitro and in vivo, providing the first targeted treatment strategy for these severe pediatric encephalopathies.

DOI10.15252/emmm.202012354
Alternate JournalEMBO Mol Med
PubMed ID33332765
Grant ListT32GM007739 / / CU | Weill Cornell Medical College (Weill Cornell) /
NIRG-15-363678 / / Alzheimer's Association (AA) /
/ / American Federation for Aging Research (AFAR) /
1R01-AG052505 / / HHS | NIH | National Institute on Aging (NIA) /
1R01-NS095988 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
R01-NS102181 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
/ / American Epilepsy Society (AES) /
R01-NS113960 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
/ / Sanofi (Sanofi US) /
1F30HD100096-01A1 / / HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) /
1F30HD100096-01A1 / / Weill Cornell /
1R01-AG052505 / / Weill Cornell /
1R01-NS095988 / / Weill Cornell /
R01-NS102181 / / Weill Cornell /
R01 / / Weill Cornell /
NS113960 / / Weill Cornell /
/ / Epilepsy Foundation /
/ / American Epilepsy Society /
/ / Leon Levy Foundation /
/ / Sanofi /