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Updated: Jun 25, 2025
08:40
Millisecond Hydrogen/Deuterium-Exchange Mass Spectrometry for the Study of Alpha-Synuclein Structural Dynamics Under Physiological Conditions
Published on: June 23, 2022
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Catechol-induced covalent modifications modulate the aggregation tendency of α-synuclein: An in-solution and
Ilenia Inciardi1, Elena Rizzotto1, Francesco Gregoris2
1Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Biofactors (Oxford, England)
|May 27, 2024
Summary
3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) inhibit alpha-Synuclein aggregation, a key factor in Parkinson's disease (PD). These compounds disrupt fibril formation by forming off-pathway oligomers and inducing covalent modifications.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Parkinson's disease (PD) is a neurodegenerative disorder characterized by Lewy Bodies (LBs) containing aggregated alpha-Synuclein (Syn).
- Targeting Syn aggregation is a key therapeutic strategy for PD.
Purpose of the Study:
- To investigate the effects of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) on Syn aggregation.
- To elucidate the mechanisms by which DOPAC and DOPET inhibit Syn fibril formation.
Main Methods:
- Proteolysis studies and mass spectrometry (MS) to identify Syn modifications.
- Molecular dynamics (MD) simulations to analyze the impact of covalent modifications on Syn aggregation.
Main Results:
- DOPAC and DOPET impede Syn fibril formation by promoting off-pathway oligomers via noncovalent interactions.
- Potential covalent modifications of Syn by DOPAC were identified.
- MD simulations revealed that covalent adducts on Syn residues enhance fibril flexibility and influence monomeric interactions.
Conclusions:
- DOPAC and DOPET show therapeutic potential for Parkinson's disease by inhibiting Syn aggregation.
- Covalent modifications induced by DOPAC alter Syn aggregation dynamics and protein structure.
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