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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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Interactions between calcium and alpha-synuclein in neurodegeneration
Alex Rcom-H'cheo-Gauthier1, Jacob Goodwin2, Dean L Pountney3
1Griffith Health Institute, School of Medical Science, Griffith University, Gold Coast, Queensland 4222, Australia. alexandre.rcom-hcheo-gauthier@griffithuni.edu.au.
Biomolecules
|September 27, 2014
Summary
Transient increases in intracellular calcium (Ca2+) trigger alpha-synuclein (α-syn) aggregation in Parkinson's disease models. This calcium-induced aggregation is exacerbated by oxidative stress and linked to neurotoxicity.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Parkinson's disease (PD) and related disorders involve alpha-synuclein (α-syn) protein aggregation.
- Triggers for pathological α-syn aggregation include post-translational modifications, oxidative stress, and elevated metal ions like calcium (Ca2+).
Purpose of the Study:
- To investigate the role of intracellular Ca2+ in inducing α-syn aggregation.
- To explore the combined effects of Ca2+ and oxidative stress on α-syn aggregation.
- To examine the relationship between Ca2+ levels, α-syn aggregation, and neuronal survival in a PD model.
Main Methods:
- Utilized cell culture models to study Ca2+-induced α-syn aggregation.
- Employed Ca2+ buffering agents (BAPTA-AM) and channel blockers (Trimethadione) to inhibit aggregation.
- Investigated α-syn aggregation in a unilateral mouse lesion model of PD, assessing neuronal survival (calbindin-positive neurons).
Main Results:
- Transient increases in intracellular Ca2+ were found to induce cytoplasmic α-syn aggregates in cell culture.
- Ca2+-dependent α-syn aggregation was successfully blocked by BAPTA-AM and Trimethadione.
- Combined elevated Ca2+ and oxidative stress synergistically increased the proportion of cells with α-syn aggregates.
- In the mouse model, α-syn aggregates were predominantly found in calbindin-negative neurons, while calbindin-positive neurons showed greater survival.
Conclusions:
- Intracellular Ca2+ plays a significant role in promoting α-syn aggregation.
- Ca2+ and oxidative stress act cooperatively to drive α-syn aggregation, a key process in neurodegeneration.
- Findings suggest a link between elevated Ca2+, α-syn aggregation, and neurotoxicity in Parkinson's disease pathologies.
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