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Published on: August 28, 2016
The mitochondrial chaperone protein TRAP1 mitigates α-Synuclein toxicity
Erin K Butler1, Aaron Voigt, A Kathrin Lutz
1Department of Neurology, University Medical Center, RWTH Aachen, Germany.
Plos Genetics
|February 10, 2012
Summary
Mitochondrial chaperone TRAP1 protects against alpha-Synuclein toxicity. Overexpressing TRAP1 in flies, rats, and human cells rescues neurotoxicity and mitochondrial dysfunction caused by alpha-Synuclein.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Alpha-Synuclein (α-Synuclein) aggregation is linked to neurodegenerative diseases.
- Mitochondrial dysfunction is a key factor in α-Synuclein toxicity.
- Genetic modifiers of α-Synuclein neurotoxicity are crucial for understanding disease mechanisms.
Purpose of the Study:
- To identify novel genetic modifiers of human [A53T]α-Synuclein-induced neurotoxicity using a whole-genome screen in Drosophila melanogaster.
- To investigate the role of the mitochondrial chaperone tumor necrosis factor receptor associated protein-1 (TRAP1) in α-Synuclein toxicity.
- To determine if TRAP1 can mitigate α-Synuclein-induced mitochondrial dysfunction and neurotoxicity.
Main Methods:
- Whole-genome screening in Drosophila melanogaster to identify genetic modifiers of [A53T]α-Synuclein neurotoxicity.
- Assessing fly climbing ability, dopamine neuron number, and sensitivity to oxidative stress.
- Overexpression and knockdown studies of TRAP1 in Drosophila, rat primary cortical neurons, and human cell lines (HEK293, SH-SY5Y).
- Measuring mitochondrial Complex I activity and observing mitochondrial morphology.
Main Results:
- Decreased TRAP1 expression exacerbated age-dependent loss of dopamine and DA neurons, impaired climbing ability, and increased oxidative stress sensitivity in [A53T]α-Synuclein flies.
- Overexpression of human TRAP1 rescued these phenotypes in flies and protected rat neurons from rotenone-induced toxicity.
- TRAP1 overexpression blocked [A53T]α-Synuclein-induced reduction in Complex I activity and prevented mitochondrial morphological alterations in human cells.
- Knockdown of TRAP1 in human cell lines enhanced sensitivity to oxidative stress.
Conclusions:
- [A53T]α-Synuclein toxicity is closely linked to mitochondrial dysfunction.
- The mitochondrial chaperone TRAP1 plays a protective role against α-Synuclein-induced neurotoxicity and mitochondrial damage.
- TRAP1 overexpression offers a potential therapeutic strategy for α-Synucleinopathies.
- TRAP1's interaction with PINK1 suggests a potential pathway linking PINK1 to α-Synuclein.
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