Amelioration of pathologic alpha-synuclein-induced Parkinson's disease by irisin
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA(2022)
摘要
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.
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关键词
irisin,Parkinson's disease,neurodegeneration,synuclein
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