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Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
Raised calcium and oxidative stress cooperatively promote alpha-synuclein aggregate formation
J Goodwin1, S Nath, Y Engelborghs
1School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast, Australia.
Neurochemistry International
|November 20, 2012
Summary
Raised calcium and oxidative stress cooperatively promote alpha-synuclein aggregation in Parkinson's disease models. This combined effect, observed both in vitro and in vivo, highlights oxidative stress's role in calcium-dependent alpha-synuclein clumping.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Cell loss in Parkinson's and Parkinson's-plus diseases is associated with aggregated alpha-synuclein (α-syn).
- Factors contributing to α-syn aggregation include oxidative stress and calcium dysregulation.
- Previous studies indicated that elevated calcium levels can promote α-syn aggregation.
Purpose of the Study:
- To investigate the combined effects of elevated calcium and oxidative stress on α-syn aggregation.
- To determine if calcium and oxidative stress interact synergistically to induce α-syn aggregation in vitro and in vivo.
Main Methods:
- In vitro experiments involved treating monomeric α-syn with calcium, hydrogen peroxide, or both.
- Techniques used included size exclusion chromatography, fluorescence correlation spectroscopy, atomic force microscopy, and scanning electron microscopy.
- In vivo cell culture experiments used human cells expressing α-syn-GFP, treated with agents to increase intracellular calcium (thapsigargin, ionophore A23187) and/or hydrogen peroxide.
Main Results:
- In vitro data showed a cooperative interaction between calcium and oxidation, leading to α-syn oligomers.
- In cell culture, both elevated intracellular calcium and hydrogen peroxide individually increased α-syn aggregates.
- Combined treatment of elevated calcium and oxidative stress significantly increased the proportion of cells with multiple α-syn focal accumulations compared to calcium alone.
Conclusions:
- Calcium and oxidative stress cooperatively promote α-syn aggregation both in vitro and in vivo.
- Oxidative stress appears to play a significant role in the calcium-dependent mechanism of α-syn aggregation.
- These findings suggest potential therapeutic targets for mitigating α-syn aggregation in neurodegenerative diseases.
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