The Therapeutic/Protective Effect And Mechanism Of Irisin In Parkinson’s Disease

Parkinson’s disease(PD)is an age-related and the second most common neurodegenerative disorder.Currently,the main therapeutic method for PD is anti-Parkinson medications,including levodopa and madopar,etc.However,the effect of pharmacological treatment has its own limitations,as the therapeutic effect of drug treatment gradually diminishes with time.Exercise has been proposed as a non-pharmacological management for people who are in the early stages of PD or people who are experiencing balance or motor function problems.Various types of exercise have been reported to effectively improve motor disorders(including balance,gait,risk of falls and physical function)and nonmotor disorders(such as sleep impairments,cognitive function,depression and anxiety)in PD patients.Nowadays,the mechanisms of benefits from exercise in PD patients have captured increasing attention.Exercise training is known to enhance neuronal functions.And the recognized mechanisms by which exercise improves brain function include neurotrophic factors,neurogenesis,neuroplasticity,neuroinflammation,mitochondrial function and oxidative stress.Recent advances show that skeletal muscles produce myokines in response to exercise,which allows for crosstalks between muscles and other organs,including brain,adipose tissue,bone,liver,gut,pancreas,vascular bed,and skin,as well as communication within the muscles themselves.Among these myokines,irisin could be regarded as an extremely promising myokine,since the effect of peripheral irisin injection in mice was very similar to that led by endurance exercise.Fibronectin-domain Ⅲ containing 5(FNDC5,which encodes the peroxisome proliferator-activated receptor-γ coactivator-1α,PGC-1α-dependent myokine irisin)is a glycosylated type 1 membrane protein,and has been identified as an important exercise-regulated factor inducing major metabolic benefits.FNDC5 is cleaved and the N-terminal portion of it is released into the circulation;the secreted form of FNDC5 has been named irisin.Irisin contains 112 amino acids,is heavily glycosylated and is 100% conserved between mouse and human.The structure of irisin and its elevation with endurance exercise in humans has been confirmed using tandem mass spectrometry of human plasma.In bones and fat tissues,irisin mediates its effects via αV integrin receptors and following FAK/Akt signaling pathway.Since the discovery as a PGC-1α-dependent myokine in 2012,irisin has been given great expectations on the management of numerous diseases.The roles of irisin in improving cognitive,memory and learning function in Alzheimer’s disease(AD)have already been described in previous studies,and elevation of circulating irisin levels by peripheral delivery could pass through the blood–brain barrier and result in enrichment of central irisin which ameliorated both the cognitive deficit and neuropathology in AD mouse models.Although research on irisin is in full swing,the role of irisin in PD remains unknown.Therefore,we carried out this study to explore the role of irisin in PD.In clinical research,this study retrospectively analyzed the relationship between motor symptom of PD patients who received regular rehabilitation exercise and the concentration of irisin in peripheral blood of those PD patients.At the same time,combining PD models with transcriptome sequencing,immunofluorescence staining,immunoblotting,transmission electron microscopy and other methods,we evaluated the effects of irisin on motor symptom,dopaminergic neuron degeneration,and mitochondrial function in PD models.In this study,we found for the first time that serum irisin levels of PD patients were markedly elevated after 12-week regular exercise,which had a positive correlation with improved balance function scored by Berg Balance Scale(BBS).Treatment with exogenous irisin could improve motor function,and reduce dopaminergic neurodegeneration in PD models.Meanwhile,the results revealed that exogenous irisin conferred neuroprotection in PD by relieving apoptosis and oxidative stress,restraining mitochondrial fragmentation,and promoting mitochondrial respiration and biogenesis.Combining with transcriptome sequencing analysis and experiments,it was found that irisin could restore the damaged Akt signaling pathway and ERK1/2 signaling pathway in PD models.At the same time,the results also showed that the way that irisin works in this study is not through endocytosis,but through binding to the integrin receptor αV subunit on the cell membrane to activate downstream signaling pathways.With the use of small-molecule inhibitors,it was found that irisin can reduce apoptosis,restore normal mitochondrial biogenesis,and improve mitochondrial morphology and dynamic balance in PD models by activating Akt and ERK1/2 signaling pathways.And irisin reduced oxidative stress via activating ERK1/2 signaling pathway.Furthermore,irisin regulated the aforementioned aspects by upregulating the Akt signaling pathway and ERK1/2signaling pathway following integrin receptors rather than directly targeting mitochondria after transported into cytoplasm.The results showed that the exercise-induced up-regulation of peripheral blood irisin concentration in PD patients was indeed related to balance function.And exogenous irisin reduces apoptosis and oxidative stress by binding to integrin receptors to activate downstream signaling pathways,inhibits mitochondrial fragmentation,restores mitochondrial morphology,and promotes mitochondrial respiration and biogenesis.Irisin not only has clinical significance,but also plays a protective and therapeutic role in PD models,which can be achieved by peripheral intraperitoneal injection.Therefore,peripherally delivered irisin may be an emerging and promising candidate for PD therapy.