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J Cell Biol. 2016 Sep 12;214(6):705-18. doi: 10.1083/jcb.201512016. Epub 2016 Sep 5.

Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation.

Author information

1
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
2
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia Single Molecule Sciences Centre, European Molecular Biology Laboratory Australia, The University of New South Wales, Sydney 2052, Australia.
3
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
4
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia Single Molecule Sciences Centre, European Molecular Biology Laboratory Australia, The University of New South Wales, Sydney 2052, Australia f.meunier@uq.edu.au y.gambin@unsw.edu.au.

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.

PMID:
27597756
PMCID:
PMC5021092
DOI:
10.1083/jcb.201512016
[Indexed for MEDLINE]
Free PMC Article

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