α-Synuclein Aggregates in the Nigro-Striatal Dopaminergic Pathway Impair Fine Movement: Partial Reversal by the Adenosine A2A Receptor Antagonist
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Published:2023-01-10
Issue:2
Volume:24
Page:1365
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Cai Qionghui,Xu Na,He Yan,Zhu Jiamin,Ye Fenfen,Luo Zhi,Lu Ruojun,Huang Linshan,Zhang Feiyang,Chen Jiang-Fan,Li Yan
Abstract
Parkinson’s disease (PD) is characterized pathologically by abnormal aggregation of alpha-synuclein (α-Syn) in the brain and clinically by fine movement deficits at the early stage, but the roles of α-Syn and associated neural circuits and neuromodulator bases in the development of fine movement deficits in PD are poorly understood, in part due to the lack of appropriate behavioral testing paradigms and PD models without motor confounding effects. Here, we coupled two unique behavioral paradigms with two PD models to reveal the following: (i) Focally injecting α-Syn fibrils into the dorsolateral striatum (DLS) and the transgenic expression of A53T-α-Syn in the dopaminergic neurons in the substantia nigra (SN, PITX3-IRES2-tTA/tetO-A53T mice) selectively impaired forelimb fine movements induced by the single-pellet reaching task. (ii) Injecting α-Syn fibers into the SN suppressed the coordination of cranial and forelimb fine movements induced by the sunflower seed opening test. (iii) Treatments with the adenosine A2A receptor (A2AR) antagonist KW6002 reversed the impairment of forelimb and cranial fine movements induced by α-Syn aggregates in the SN. These findings established a causal role of α-Syn in the SNc-DLS dopaminergic pathway in the development of forelimb and cranial fine movement deficits and suggest a novel therapeutic strategy to improve fine movements in PD by A2AR antagonists.
Funder
the Natural Science Foundation of Zhejiang Province of China grant
the National Natural Science Foundation of China grant
the Ministry of Science and Technology of the People’s Republic of China grant
the Startup Fund from Wenzhou Medical University
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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