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

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.

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by progressive worsening of motor symptoms, including bradykinesia, resting tremor, and rigidity (1, 2). Nonmotor symptoms often precede and accompany the motor symptoms and include autonomic dysfunction and neuropsychiatric sequelae (3). The most notable loss of neurons occurs in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), although neuronal loss also occurs in the locus coeruleus, dorsal raphe nucleus, the dorsal motor nucleus of the vagus, and nucleus basalis of Meynert (4). In addition to neuronal loss, there is accumulation of misfolded pathologic α-synuclein that drives the pathogenesis of PD, including the neuronal dysfunction and the ultimate of neuronal degeneration (5, 6). Current treatments for PD include the replacement of dopamine (DA) via L-DOPA, DA agonists, and other agents to treat the nonmotor symptoms. As the disease progresses, deep brain stimulation and other neurosurgical approaches can be used to treat the side effects of DA replacement therapy. Importantly, these treatments only address the symptomology, and over time there is a progressive decline in normal function. Moreover, there are no treatments that slow the progression or inhibit the underlying drivers of PD pathogenesis. As such, treatments that result in durable arrest of PD symptoms are urgently needed.Irisin is a small polypeptide that is secreted by skeletal muscle and other tissues into the blood of mice and humans (7, 8). The amino acid sequence is conserved 100% between mice and humans, suggesting a critical, conserved function. Importantly, the expression of irisin and its precursor protein FNDC5 is increased in muscle in response to many forms of exercise, both in rodents and in humans. Irisin levels increase in the blood of humans with exercise training, as determined by tandem mass spectrometry (8). In adipose cells, osteocytes, osteoclasts, and astrocytes integrin αV/β5 is the major functioning receptor for irisin (9, 10).Physical activity can prevent and ameliorate the symptoms of multiple forms of neurodegeneration, including Alzheimer’s disease (AD) and PD (11–14). Since irisin carries some of the benefits of exercise to adipose tissues, we and others have begun to study the effects of irisin in various models of neurodegeneration. In the earliest study, we showed that elevated expression of FNDC5 in the liver via the use of adenoviral vectors, and presumptive elevations of irisin in the blood, stimulated an “exercise-like” program of gene expression in the hippocampus (15). Moreover, the expression of FNDC5 with these same viral vectors rescued memory deficits in a mouse model of AD (16). Most recently, irisin itself was shown to be the active moiety regulating cognitive function in four separate mouse models. Importantly, elevation of the blood levels of the mature, cleaved irisin using adeno-associated virus (AAV) was sufficient to improve cognitive function and reduce neuroinflammation in two distinct models of AD (9). Furthermore, irisin itself crossed the blood–brain barrier (BBB), at least when the protein was produced from the liver with these AAV vectors.In the current study, we examine the effects of irisin on the pathophysiology of PD, using the α-synuclein preformed fibril (α-syn PFF) seeding model in vitro and in vivo. Pathologic α-syn is thought to spread “prion-like” in the brains of PD patients and certain other neurological disorders, where they cause neuronal death and dysfunction. We show here that irisin has powerful effects in preventing both the accumulation of pathologic α-syn and neuronal cell death in primary cell culture. Furthermore, elevation of blood irisin levels in mice normalizes the histological manifestations in the SNpc and the PD-like symptomology involving movement and grip strength induced by intrastriatal injection of α-syn PFF. Together, these data suggest the potential therapeutic value of irisin in PD and other neurodegenerative states that involve α-syn.