Construction of a Rat Model of Hemilateral Parkinson’s Disease Induced by Human Wild-Type α-Synuclein Overexpression

Qi Pan,1,* Jianyue Lu,2,* Zongyu Xiao,3 Huaming Zhang,4 Guanghao Liu,4 Yiying Li5,* 1Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 2International School, Sehan University, Youngam-gun, 58447, Republic of Korea; 3Department of Neurosurgery, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215124, People’s Republic of China; 4Department of Neurosurgery, the First Affiliated Hospital of Hainan Medical University, Haikou, 570102, People’s Republic of China; 5Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, 571199, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiying Li, Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, 3# Xueyuan Road, Longhua District, Haikou, Hainan Province, 571199, People’s Republic of China, Tel +8689865732303, Email [email protected]: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. The precise etiology and pathogenesis of PD remain unclear. Human wild-type α-synuclein has been implicated in PD pathogenesis. The objective of this study is to examine the role of α-synuclein in PD by establishing a rat model of substantia nigra degeneration and Motor behavioral changes through the induced overexpression of human α-synuclein.Methods: Rats were randomly assigned to either the Negative control group or the adeno-associated virus serotype 9 (AAV9) treatment group. Animals in the AAV9 group received 2.5 μL of AAV9 expressing human wild-type α-synuclein, while those in the Negative control group received an equal volume of AAV9 expressing green fluorescent protein via stereotactic unilateral injection into the substantia nigra pars compacta. Behavioral assessments were conducted at 1-, 3-, and 8-weeks following virus administration. Tyrosine hydroxylase and human α-synuclein expression in the substantia nigra pars compacta were analyzed. Additionally, dopamine, dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum were quantified.Results: After 3 weeks of virus induction, neurodegeneration of the right substantia nigra was observed, with a reduction in the number of tyrosine hydroxylase-immunopositive neurons in the AAV9 group. By 8 weeks, substantia nigra neurodegeneration had further progressed, and animals in the AAV9 group exhibited apomorphine-induced asymmetrical rotation and altered forelimb use.Conclusion: Overexpression of human wild-type α-synuclein led to substantia nigra degeneration and Motor behavioral changes in rats, providing a viable model for exploring the pathogenesis of Parkinson’s disease. Limitations include the 8-week observation window and the absence of neuroinflammation markers.Keywords: α-Synuclein, dopaminergic neurons, Parkinson’s disease, pathogenesis, substantia nigra