An accelerated Parkinson's disease monkey model using AAV-a-synuclein plus Poly(ADP-ribose)

The etiology of Parkinson's disease (PD) remains elusive, and the limited availability of suitable animal models hampers research on pathogenesis and drug development. We report the development of a cynomolgus monkey model of PD that combines AAV-mediated overexpression of a-synuclein into the substantia nigra with injection of Poly(ADP-ribose) (PAR) into the striatum. Our results show that pathological processes were accelerated, including dopaminergic neuron degeneration, Lewy Bodies aggregation, and hallmarks of inflammation in microglia and astrocytes. Behavioral phenotypes, dopamine transporter imaging and transcriptomic profiling further demonstrate consistencies between the model and PD patients. This model can help to determine mechanisms underlying PD impacted by a-synuclein and PAR and aid in accelerated development of therapeutic strategies for PD. Overall design: This paper can solve the limitations of the existing PD monkey model, including the drug-induced model cannot simulate Lewy body pathology in PD patients, and the current etiological PD model cannot simulate behavioral phenotype and glia inflammation. Our etiological monkey model utilizes PAR to accelerate pathological processes and behavioral phenotypes, which are closer to that of PD patients, which is significant for preclinical research on PD treatment strategies.