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

Chai, Ye Jin, Sierecki, Emma, Tomatis, Vanesa M., Gormal, Rachel S., Giles, Nichole, Morrow, Isabel C., Xia, Di, Götz, Jürgen, Parton, Robert G., Collins, Brett M., Gambin, Yann and Meunier, Frédéric A. (2016) Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation. The Journal of Cell Biology, 214 6: 705-718. doi:10.1083/jcb.201512016

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Author Chai, Ye Jin
Sierecki, Emma
Tomatis, Vanesa M.
Gormal, Rachel S.
Giles, Nichole
Morrow, Isabel C.
Xia, Di
Götz, Jürgen
Parton, Robert G.
Collins, Brett M.
Gambin, Yann
Meunier, Frédéric A.
Title Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation
Journal name The Journal of Cell Biology   Check publisher's open access policy
ISSN 0021-9525
1540-8140
Publication date 2016-09-05
Year available 2016
Sub-type Article (original research)
DOI 10.1083/jcb.201512016
Open Access Status File (Publisher version)
Volume 214
Issue 6
Start page 705
End page 718
Total pages 14
Place of publication New York, United States
Publisher Rockefeller University Press
Language eng
Abstract 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.
Formatted 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-SynWT and that of the Parkinson’s disease–causing α-SynA30P mutant, an effect rescued by Munc18-1WT expression, indicative of chaperone activity. Coexpression of the α-SynA30P mutant with Munc18-1 reduced the number of α-SynA30P 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.
Keyword Munc18-1
Neurotransmitter release
α-synuclein
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID GNT1044014GNT
Institutional Status UQ

 
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Created: Fri, 30 Sep 2016, 23:08:45 EST by Susan Allen on behalf of Institute for Molecular Bioscience