Targeted stabilization of Munc18-1 function via pharmacological chaperones.
Targeted stabilization of Munc18-1 function via pharmacological chaperones.
复制标题
通过药理伴侣靶向稳定Munc18-1功能。
DOI：
10.15252/emmm.202012354
复制
发表时间：
2021-01-11
影响因子：
11.1
通讯作者：
Burré J
中科院分区：
文献类型：
--
作者：
Abramov D;Guiberson NGL;Daab A;Na Y;Petsko GA;Sharma M;Burré J
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. This study presents a novel treatment strategy for the severe epileptic encephalopathies associated with Munc18‐1 mutations. Using an in silico screen followed by validations in mouse neurons and C. elegans models, three compounds that target Munc18‐1 and reverse neuronal dysfunction are identified.
