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

Proc Natl Acad Sci U S A. 2022 Sep 6;119(36):e2204835119. doi: 10.1073/pnas.2204835119. Epub 2022 Aug 31.


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.

Keywords: Parkinson’s disease; irisin; neurodegeneration; synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum* / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Fibronectins* / administration & dosage
  • Fibronectins* / genetics
  • Fibronectins* / metabolism
  • Mice
  • Parkinson Disease* / metabolism
  • Parkinson Disease* / therapy
  • alpha-Synuclein* / genetics
  • alpha-Synuclein* / metabolism


  • FNDC5 protein, mouse
  • Fibronectins
  • alpha-Synuclein