Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Parkinson's disease (PD) pathogenesis is linked to alpha synuclein (aSyn) aggregation.
• A novel H50Q mutation in aSyn has been identified in PD patients.
• Histidine 50 (H50) is a target for lipid peroxidation product 4-hydroxy-2-nonenal (HNE), promoting aSyn toxicity.

Purpose of the Study:

• To elucidate the role of H50 in HNE-mediated aSyn aggregation and toxicity.
• To investigate the impact of H50 mutation on aSyn pathology, including H50Q and H50R mutations.

Main Methods:

• In vitro analysis of HNE-modified aSyn.
• Cell-based experiments using H4 neuroglioma cells overexpressing wild-type and mutant aSyn (H50Q, H50R).
• Assessment of aSyn oligomerization, fibril formation, and cell death.

Main Results:

• H50 is the primary site for HNE modification and is crucial for HNE-induced aSyn oligomerization and toxicity.
• H50Q/R mutations significantly increase aSyn aggregation, fibril formation, and potentiate oligomerization.
• Overexpression of H50Q/R aSyn mutants in cells increases cell death, exacerbated by H2O2.

Conclusions:

• Alterations at H50, through posttranslational modification or mutation, trigger aSyn aggregation and toxicity.
• H50 plays a critical role in the pathogenesis of both sporadic and monogenic Parkinson's disease.