TY - JOUR
T1 - Targeted stabilization of Munc18-1 function via pharmacological chaperones
AU - Abramov, Debra
AU - Guiberson, Noah Guy Lewis
AU - Daab, Andrew
AU - Na, Yoonmi
AU - Petsko, Gregory A.
AU - Sharma, Manu
AU - Burré, Jacqueline
N1 - 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.
PY - 2021/1/11
Y1 - 2021/1/11
N2 - 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.
AB - 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.
KW - Munc18-1
KW - pharmacological chaperone
KW - Rescue
KW - small molecule
KW - STXBP1
UR - http://www.scopus.com/inward/record.url?scp=85097607172&partnerID=8YFLogxK
U2 - 10.15252/emmm.202012354
DO - 10.15252/emmm.202012354
M3 - Article
C2 - 33332765
AN - SCOPUS:85097607172
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4684
IS - 1
M1 - e12354
ER -