ArticleEMBO molecular medicine2021
Targeted stabilization of Munc18-1 function via pharmacological chaperones.
Article in EMBO molecular medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed, 23 citations in OpenAlex.
- Disease-linked mutations in Munc18-1 deplete synaptic Doc2.Brain : a journal of neurology · 2024Article
- Article
- Article
- Reduced MUNC18-1 Levels, Synaptic Proteome Changes, and Altered Network Activity inBiological psychiatry global open science · 2024Article
- Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability.Cell reports. Medicine · 2023Article
- Review
- Forty years of the adrenal chromaffin cell through ISCCB meetings around the world.Pflugers Archiv : European journal of physiology · 2023Review
- Clinical variants inGenetics in medicine open · 2023Article
- Assessing the landscape of STXBP1-related disorders in 534 individuals.Brain : a journal of neurology · 2022Article
- Targeted stabilization of Munc18-1 function via pharmacological chaperones.EMBO molecular medicine · 2021Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.