C-Terminal Radical Oxidation Inhibits α-Synuclein Aggregation and Cytotoxicity via an Oxidative Oligomer-Disrupting...

Area of Science:

• Biochemistry
• Neuroscience
• Oxidative Stress Research

Background:

• Alpha-synuclein (α-Syn) aggregation is central to Parkinson's disease (PD) pathogenesis.
• Oxidative stress is implicated in neurodegenerative disorders, often exacerbating protein aggregation.
• Understanding α-Syn's response to oxidative modifications is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the impact of controlled radical oxidation on α-Syn aggregation and cytotoxicity.
• To explore the potential of targeted oxidative modification as a neuroprotective strategy.
• To elucidate the mechanisms by which radical oxidation affects α-Syn oligomerization.

Main Methods:

• Utilized a microscale low-temperature plasma device for submillisecond radical oxidation.
• Employed native ion mobility-mass spectrometry and liquid chromatography-tandem mass spectrometry for analysis.
• Assessed cytotoxicity in SH-SY5Y cells following α-Syn oxidation.

Main Results:

• Demonstrated preferential C-terminal oxidation of α-Syn by radicals.
• Showed that targeted oxidation inhibits α-Syn aggregation and reduces cytotoxicity.
• Confirmed the inhibitory effect is specific to monomer oxidation, not preformed aggregates.

Conclusions:

• Ultrafast C-terminal radical oxidation disrupts α-Syn oligomerization, preventing fiber formation.
• This study reveals a novel oxidative pathway that modulates α-Syn fibrillization.
• Findings challenge the solely detrimental view of oxidative stress in α-Syn pathology and suggest neuroprotective applications.