-Synuclein Aggregates in the Nigro-Striatal Dopaminergic Pathway Impair Fine Movement: Partial Reversal by the Adenosine A_2A Receptor Antagonist

Parkinson's disease (PD) is characterized pathologically by abnormal aggregation of alpha-synuclein (alpha-Syn) in the brain and clinically by fine movement deficits at the early stage, but the roles of alpha-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 alpha-Syn fibrils into the dorsolateral striatum (DLS) and the transgenic expression of A53T-alpha-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 alpha-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 A(2A) receptor (A(2A)R) antagonist KW6002 reversed the impairment of forelimb and cranial fine movements induced by alpha-Syn aggregates in the SN. These findings established a causal role of alpha-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 A(2A)R antagonists.