Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin

Physical activity provides clinical benefit in Parkinson's disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic alpha-synuclein (alpha-syn)-induced neurodegeneration in the alpha-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of alpha-syn PFF cause a reduction in the formation of pathologic alpha-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the alpha-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated alpha-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of alpha-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic alpha-syn by enhancing endolysosomal degradation of pathologic alpha-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.