Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin.
Proc Natl Acad Sci U S A
; 119(36): e2204835119, 2022 09 06.
Article
em En
| MEDLINE
| ID: mdl-36044549
ABSTRACT
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 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. Our findings highlight the potential for therapeutic disease modification of irisin in PD.
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Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
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Fibronectinas
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Corpo Estriado
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Alfa-Sinucleína
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article