Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation
Ye Jin Chai, Emma Sierecki, Vanesa M Tomatis, Rachel S Gormal, Nichole Giles, Isabel C Morrow, Di Xia, Jürgen Götz, Robert G Parton, Brett M Collins, Yann Gambin, Frédéric A Meunier, Ye Jin Chai, Emma Sierecki, Vanesa M Tomatis, Rachel S Gormal, Nichole Giles, Isabel C Morrow, Di Xia, Jürgen Götz, Robert G Parton, Brett M Collins, Yann Gambin, Frédéric A Meunier
Abstract
Munc18-1 is a key component of the exocytic machinery that controls neurotransmitter release. Munc18-1 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 Munc18-1 EIEE-causing mutants form large polymers that coaggregate wild-type Munc18-1 in vitro and in cells. Surprisingly, Munc18-1 EIEE mutants also form Lewy body-like structures that contain α-synuclein (α-Syn). We reveal that Munc18-1 binds α-Syn, and its EIEE mutants coaggregate α-Syn. Likewise, removal of endogenous Munc18-1 increases the aggregative propensity of α-Syn(WT) and that of the Parkinson's disease-causing α-Syn(A30P) mutant, an effect rescued by Munc18-1(WT) expression, indicative of chaperone activity. Coexpression of the α-Syn(A30P) mutant with Munc18-1 reduced the number of α-Syn(A30P) aggregates. Munc18-1 mutations and haploinsufficiency may therefore trigger a pathogenic gain of function through both the corruption of native Munc18-1 and a perturbed chaperone activity for α-Syn leading to aggregation-induced neurodegeneration.
© 2016 Chai et al.
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References
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