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The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity
Ossama Khalaf1, Bruno Fauvet1, Abid Oueslati1
1From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and.
The Journal of Biological Chemistry
|June 18, 2014
Summary
The H50Q mutation in alpha-synuclein (α-Syn) accelerates protein aggregation and increases its secretion, contributing to cell death in Parkinson disease (PD) models.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Missense mutations in the alpha-synuclein (α-Syn) gene SNCA are linked to inherited Parkinson disease (PD).
- A novel H50Q missense mutation in α-Syn has been identified in familial PD and dementia cases.
Purpose of the Study:
- To investigate the biophysical properties and cellular consequences of the novel H50Q α-Syn mutation.
- To understand the role of this mutation in Parkinson disease pathogenesis.
Main Methods:
- In vitro studies on α-Syn structure, metal interaction, and phosphorylation.
- In vitro fibrillization assays.
- Cell-based models (SHSY5Y cells, hippocampal neurons) assessing localization, phosphorylation, secretion, mitochondrial fragmentation, and cell death.
Main Results:
- H50Q mutation accelerated α-Syn fibrillization in vitro but did not alter monomer structure or phosphorylation.
- H50Q increased α-Syn secretion from cells and induced mitochondrial fragmentation in neurons.
- Both wild-type and H50Q α-Syn were toxic when extracellular, with H50Q showing enhanced toxicity.
Conclusions:
- The H50Q mutation enhances α-Syn aggregation and extracellular secretion, contributing to its toxicity in Parkinson disease.
- This mutation provides new insights into the pathogenic mechanisms of PD and related disorders.
