Targeted stabilization of Munc18-1 function via pharmacological chaperones

Debra Abramov; Noah Guy Lewis Guiberson; Andrew Daab; Yoonmi Na; Gregory A. Petsko; Manu Sharma; Jacqueline Burré

doi:10.15252/emmm.202012354

Targeted stabilization of Munc18-1 function via pharmacological chaperones

Debra Abramov, Noah Guy Lewis Guiberson, Andrew Daab, Yoonmi Na, Gregory A. Petsko, Manu Sharma, Jacqueline Burré

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

12 Citations (SciVal)

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.

Original language	English
Article number	e12354
Journal	EMBO Molecular Medicine
Volume	13
Issue number	1
Early online date	17 Dec 2020
DOIs	https://doi.org/10.15252/emmm.202012354
Publication status	Published - 11 Jan 2021

Bibliographical note

Funding Information:
We thank Dr. Thomas C. Südhof for providing antibodies and Dr. Matthijs Verhage for providing the conditional Munc18‐1 knockout mice. This work was supported by T32GM007739 (Weill Cornell/Rockefeller/Sloan Kettering Tri‐Institutional MD PhD Program for D.A.), 1F30HD100096‐01A1 (to D.A.), the Alzheimer’s Association (NIRG‐15‐363678 to M.S.), AFAR (M.S.), the NIH (1R01‐AG052505 and 1R01‐NS095988 to M.S.; R01‐NS102181 and R01‐NS113960 to J.B.), the Epilepsy Foundation & American Epilepsy Society (J.B.), the Leon Levy Foundation (J.B.), and the Sanofi Innovation Awards Program (J.B.).

Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

We thank Dr. Thomas C. Südhof for providing antibodies and Dr. Matthijs Verhage for providing the conditional Munc18‐1 knockout mice. This work was supported by T32GM007739 (Weill Cornell/Rockefeller/Sloan Kettering Tri‐Institutional MD PhD Program for D.A.), 1F30HD100096‐01A1 (to D.A.), the Alzheimer’s Association (NIRG‐15‐363678 to M.S.), AFAR (M.S.), the NIH (1R01‐AG052505 and 1R01‐NS095988 to M.S.; R01‐NS102181 and R01‐NS113960 to J.B.), the Epilepsy Foundation & American Epilepsy Society (J.B.), the Leon Levy Foundation (J.B.), and the Sanofi Innovation Awards Program (J.B.). We thank Dr. Thomas C. S?dhof for providing antibodies and Dr. Matthijs Verhage for providing the conditional Munc18-1 knockout mice. This work was supported by T32GM007739 (Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD PhD Program for D.A.), 1F30HD100096-01A1 (to D.A.), the Alzheimer?s Association (NIRG-15-363678 to M.S.), AFAR (M.S.), the NIH (1R01-AG052505 and 1R01-NS095988 to M.S.; R01-NS102181 and R01-NS113960 to J.B.), the Epilepsy Foundation & American Epilepsy Society (J.B.), the Leon Levy Foundation (J.B.), and the Sanofi Innovation Awards Program (J.B.).

Keywords

Munc18-1
pharmacological chaperone
Rescue
small molecule
STXBP1

ASJC Scopus subject areas

Molecular Medicine

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10.15252/emmm.202012354Licence: CC BY

Cite this

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title = "Targeted stabilization of Munc18-1 function via pharmacological chaperones",

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.",

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author = "Debra Abramov and Guiberson, {Noah Guy Lewis} and Andrew Daab and Yoonmi Na and Petsko, {Gregory A.} and Manu Sharma and Jacqueline Burr{\'e}",

note = "Funding Information: We thank Dr. Thomas C. S{\"u}dhof for providing antibodies and Dr. Matthijs Verhage for providing the conditional Munc18‐1 knockout mice. This work was supported by T32GM007739 (Weill Cornell/Rockefeller/Sloan Kettering Tri‐Institutional MD PhD Program for D.A.), 1F30HD100096‐01A1 (to D.A.), the Alzheimer{\textquoteright}s Association (NIRG‐15‐363678 to M.S.), AFAR (M.S.), the NIH (1R01‐AG052505 and 1R01‐NS095988 to M.S.; R01‐NS102181 and R01‐NS113960 to J.B.), the Epilepsy Foundation & American Epilepsy Society (J.B.), the Leon Levy Foundation (J.B.), and the Sanofi Innovation Awards Program (J.B.). Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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AU - Sharma, Manu

AU - Burré, Jacqueline

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Targeted stabilization of Munc18-1 function via pharmacological chaperones

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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