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

Research output: Contribution to journalArticlepeer-review

8 Citations (SciVal)


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 languageEnglish
Article numbere12354
JournalEMBO Molecular Medicine
Issue number1
Early online date17 Dec 2020
Publication statusPublished - 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 2021 Elsevier B.V., All rights reserved.


  • Munc18-1
  • pharmacological chaperone
  • Rescue
  • small molecule
  • STXBP1

ASJC Scopus subject areas

  • Molecular Medicine


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