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Urate promotes SNCA/α-synuclein clearance via regulating mTOR-dependent macroautophagy
Yu-Lan Sheng1, Xing Chen1, Xiao-Ou Hou1
1Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Institute of Neuroscience, Soochow University, Suzhou 215123, China.
Experimental Neurology
|August 20, 2017
Summary
Uric acid (UA) enhances autophagy by inhibiting mTOR, reducing alpha-synuclein accumulation in Parkinson's disease models. This suggests UA-elevating agents could be a potential Parkinson's therapy.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Serum urate levels are lower in Parkinson's disease (PD) patients, suggesting a protective role.
- The precise mechanism of urate's effect on PD pathogenesis remains unclear.
Purpose of the Study:
- To investigate the mechanism by which uric acid (UA) influences autophagy and alpha-synuclein (SNCA) accumulation in Parkinson's disease models.
- To explore the potential of UA as a therapeutic strategy for PD.
Main Methods:
- PC12 cells and SNCAA53T transgenic mice were used to study autophagy markers (LC3-II, P62) and SNCA levels.
- Experiments involved treatments with uric acid (UA), Bafilomycin A1, and an mTOR activator (3BDO).
- Autophagy activation was assessed via LC3 puncta and autophagosome/autolysosome formation.
Main Results:
- UA treatment dose- and time-dependently enhanced autophagy in PC12 cells by increasing LC3-II and decreasing P62.
- UA-induced autophagy occurred via mTOR inhibition and ULK1 activation, independent of lysosomal function.
- UA reduced SNCA/α-synuclein accumulation in vitro and in vivo, an effect blocked by lysosomal inhibition.
- UA modulated autophagy markers and reduced SNCA in the midbrain of SNCAA53T mice.
Conclusions:
- Uric acid activates autophagy through mTOR-dependent signaling, ameliorating SNCA accumulation.
- These findings support the potential of urate-elevating agents as a therapeutic strategy for Parkinson's disease.
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