Evaluation of peripheral and intranigral AAV-mediated Irisin delivery in a chronic AAV-A53T α-Synuclein overexpression mouse model of Parkinson’s disease

Background Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra and pathological aggregation of α-Synuclein (α-Syn). Although Irisin has shown neuroprotective effects in acute MPTP-induced and α-Syn preformed fibrils (PFFs) propagation models, its therapeutic effects in a chronic α-Syn overexpression model remain incompletely defined. Methods In the present study, we evaluated the effects of AAV8-Irisin delivered either peripherally via tail vein injection or centrally via direct intranigral co-administration in the AAV9-A53T mouse model. Results Under the tested doses, routes, and intervention schedule, neither peripheral nor intranigral AAV8-Irisin delivery produced statistically significant improvements in behavioral performance, dopaminergic neuron survival, α-Synuclein pathology, glial activation, or AQP4 polarization; however, numerical trends were observed in select measures, including motor coordination and TH-positive neuron counts. Conclusion These findings suggest that, under the current experimental conditions, a clear neuroprotective benefit of Irisin was not readily detectable in this model. Whether modest effects might emerge under different exposure levels, intervention windows, or adequately powered designs remains unknown.