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Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin
Tae-In Kam 1 2, Hyejin Park 1 2, Shih-Ching Chou 1 2, Jonathan G Van Vranken 3, Melanie J Mittenbühler 3 4, Hyeonwoo Kim 3 4, Mu A 3 4, Yu Ree Choi 1 2, Devanik Biswas 1 2, Justin Wang 1 2, Yu Shin 1 2, Alexis Loder 1, Senthilkumar S Karuppagounder 1 2, Christiane D Wrann 5, Valina L Dawson 1 2 6 7, Bruce M Spiegelman 3 4, Ted M Dawson 1 2 6 8
Abstract:
...Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn...
PMID: 36044549
Free Full-Text: https://www.pnas.org/doi/full/10.1073/pnas.2204835119
