Title | Targeted stabilization of Munc18-1 function via pharmacological chaperones. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Abramov D, Guiberson NGuy Lewis, Daab A, Na Y, Petsko GA, Sharma M, Burré J |
Journal | EMBO Mol Med |
Pagination | e12354 |
Date Published | 2020 Dec 17 |
ISSN | 1757-4684 |
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. |
DOI | 10.15252/emmm.202012354 |
Alternate Journal | EMBO Mol Med |
PubMed ID | 33332765 |
PubMed Central ID | PMC7799358 |
Grant List | 1R01-AG052505 / / Weill Cornell / / / Sanofi / / / American Epilepsy Society (AES) / T32GM007739 / / CU | Weill Cornell Medical College (Weill Cornell) / R01 NS102181 / NS / NINDS NIH HHS / United States 1F30HD100096-01A1 / / HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) / R01 NS113960 / NS / NINDS NIH HHS / United States R01-NS113960 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / / / Sanofi (Sanofi US) / R01 AG052505 / AG / NIA NIH HHS / United States F31 NS098623 / NS / NINDS NIH HHS / United States 1R01-NS095988 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / / / American Federation for Aging Research (AFAR) / F30 HD100096 / HD / NICHD NIH HHS / United States NIRG-15-363678 / / Alzheimer's Association (AA) / R01 / / Weill Cornell / / / Leon Levy Foundation / 1R01-AG052505 / / HHS | NIH | National Institute on Aging (NIA) / R01-NS102181 / / Weill Cornell / R01-NS102181 / / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / 1F30HD100096-01A1 / / Weill Cornell / NS113960 / / Weill Cornell / / / Epilepsy Foundation / / / American Epilepsy Society / T32 GM007739 / GM / NIGMS NIH HHS / United States R01 NS095988 / NS / NINDS NIH HHS / United States 1R01-NS095988 / / Weill Cornell / |