Munc 18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation

Munc 18-1 is a key component of the exocytic machinery that controls neurotransmitter release. Munc 18-1 heterozygous mutations cause developmental defects and epileptic phenotypes, including infantile epileptic encephalopathy (EIEE), suggestive of a gain of pathological function. Here, we used single-molecule analysis, gene-edited cells, and neurons to demonstrate that Munc 18-1 EIEE-causing mutants form large polymers that coaggregate wild-type Munc 18-1 in vitro and in cells. Surprisingly, Munc 18-1 EIEE mutants also form Lewy body like structures that contain a-synuclein (alpha-Syn). We reveal that Munc 18-1 binds alpha-Syn, and its EIEE mutants coaggregate alpha-Syn. Likewise, removal of endogenous Munc 18-1 increases the aggregative propensity of alpha-Syn(wT) and that of the Parkinson's disease-causing a-Syn(A30P) mutant, an effect rescued by Munc18-1(WT) expression, indicative of chaperone activity. Coexpression of the alpha-Syn(A30P) mutant with Munc 18-1 reduced the number of alpha-Syn(A30P) aggregates. Munc 18-1 mutations and haploinsufficiency may therefore trigger a pathogenic gain of function through both the corruption of native Munc 18-1 and a perturbed chaperone activity for a-Syn leading to aggregation-induced neurodegeneration.