Journal
JOURNAL OF PARKINSONS DISEASE
Volume 10, Issue 3, Pages 969-979Publisher
IOS PRESS
DOI: 10.3233/JPD-191909
Keywords
Fasudil; A53T alpha-synuclein; Parkinson's disease; macroautophagy; vesicular monoamine transporter 2; positron emission tomography
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Funding
- China Postdoctoral Science Foundation [2017M610227, 2018T110350]
- Ministry of Science and Technology of China [2016YFC1306500, 2016YFC1306504]
- National Nature Science Foundation of China [81771372, 81571232, 81701250]
- Shanghai Municipal Commission of Science and Technology [2018SHZDZX01, 17JC1401400]
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Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder, but the disease-modifying therapies focusing on the core pathological changes are still unavailable. Rho-associated protein kinase (ROCK) has been suggested as a promising target for developing neuroprotective therapies in PD. Objective: We aimed to explore the promotion of alpha-synuclein (alpha-syn) clearance in a rat model. Methods: In a rat model induced by unilateral injection of adeno-associated virus of serotype 9 (AAV9) expressing A53T alpha-syn (AAV9-A53T-alpha-syn) into the right substantia nigra, we aimed to investigate whether Fasudil could promote alpha-syn clearance and thereby attenuate motor impairments and dopaminergic deficits. Results: In our study, treatment with Fasudil (5 mg/kg rat weight/day) for 8 weeks significantly improved the motor deficits in the Cylinder and Rotarod tests. In the in vivo positron emission tomography imaging with the ligand F-18-dihydrotetrabenazine, Fasudil significantly enhanced the dopaminergic imaging in the injected striatum of the rat model (p < 0.05 vs. vehicle group, p < 0.01 vs. left striatum in Fasudil group). The following mechanistic study confirmed that Fasudil could promote the autophagic clearance of alpha-syn by Becline 1 and Akt/mTOR pathways. Conclusion: Our study suggested that Fasudil, the ROCK2 inhibitor, could attenuate the anatomical and behavioral lesions in the Parkinsonian rat model by autophagy activation. Our results identify Fasudil as a drug with high translational potential as disease-modifying treatment for PD and other synucleinopathies.
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