A holistic rat model to investigate therapeutic interventions in Parkinson's disease : viral induction of a slow-progressing motor phenotype, dopaminergic degeneration and early microglia neuroinflammation

Abstract

Parkinson’s disease is a chronic progressive neurodegenerative disorder, mostly manifesting in late adulthood. Patients suffering from this idiopathic disease of the nervous system develop cardinal motor symptoms that usually appear after non-motor symptoms. It is characterized by loss of dopaminergic neurons located in the substantia nigra pars compacta and formation of insoluble intracellular protein inclusions of α-synuclein (Lewy Bodies). Another symptom is neuroinflammation, which often precedes dopaminergic neuron degeneration and the formation of aggregates. In this study, we aimed to establish a viral vector-mediated rat model of Parkinson’s disease that mimics both the histological features of the disease and its slow, age-related progression, including the development of a motor phenotype over time. Evaluation of different adeno-associated viral serotypes overexpressing the human α-synuclein protein revealed that both AAV/6 and AAV/DJ equally transduce primary dopaminergic neurons in vitro with the latter being more efficient. In vivo transduction of dopaminergic neurons with AAV/DJ led to their degeneration in the substantia nigra pars compacta, which coincided with reduced dopaminergic fibers reaching the ipsilateral striatum. Microglia inflammatory response and accumulation thereof was evident at early disease stages. Simultaneously, behavioral assessment in the cylinder, the stepping and the staircase test showed a decrease in gross motor performance while rearing and stepping. Taken together, we established an early AAV/DJ-mediated model for Parkinson’s disease in rats, which not only shows histological hallmarks but due to its progressive motor phenotype also provides a therapeutic window suitable for future pharmacological modification.