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Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation
Ye Jin Chai1, Emma Sierecki2, Vanesa M Tomatis1
1Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
The Journal of Cell Biology
|September 7, 2016
Summary
Munc18-1 mutations causing infantile epileptic encephalopathy lead to protein aggregation and neurodegeneration. These mutations disrupt normal Munc18-1 function and impair its ability to prevent alpha-synuclein clumping, a hallmark of Parkinson's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Munc18-1 is crucial for neurotransmitter release.
- Mutations in Munc18-1 are linked to infantile epileptic encephalopathy (EIEE) and suggest a pathological gain of function.
Purpose of the Study:
- To investigate the molecular mechanisms underlying Munc18-1 mutations in EIEE.
- To explore the relationship between Munc18-1, alpha-synuclein (α-Syn), and neurodegeneration.
Main Methods:
- Single-molecule analysis
- Gene-edited cellular and neuronal models
- Co-immunoprecipitation assays
Main Results:
- EIEE-associated Munc18-1 mutants form polymers and coaggregate wild-type Munc18-1.
- Munc18-1 mutants form Lewy body-like structures containing α-Syn.
- Munc18-1 exhibits chaperone activity for α-Syn, and its loss-of-function exacerbates α-Syn aggregation, including Parkinson's disease-related mutants.
Conclusions:
- Munc18-1 mutations cause EIEE through a gain-of-function mechanism involving protein polymerization and α-Syn aggregation.
- Perturbed Munc18-1 chaperone activity contributes to α-Syn aggregation and neurodegeneration.
- These findings link Munc18-1 dysfunction to both epilepsy and Parkinson's disease pathology.
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