Therapeutic Potential of Irisin in Neurodegenerative Diseases

Irisin is a myokine secreted by muscle in response to exercise. It is derived from a transmembrane protein called fibronectin type III domain-containing protein 5 (FNDC5). The Fndc5 gene is expressed in several tissues, including skeletal muscle, brain, adipose tissue, heart, kidney, and lung. Irisin is cleaved from FNDC5 protein by the enzyme furin and released into circulation. In addition to exercise, several drugs have been shown to increase the production of irisin. Administration of exogenous irisin mimics the beneficial actions of exercise. Irisin can cross the blood-brain barrier and exert neuroprotective actions in the brain. It has been shown to reverse Alzheimer's pathologies in clinical and animal studies. Irisin also exerts protective effects against obesity, diabetes, and cardiovascular disease, diseases that often coexist with aging AD patients. Multiple approaches have been taken to suggest that exercise may act through irisin. Studies have provided direct evidence linking the two using Fndc5 gene deletion and irisin antibodies. Irisin binds to αVβ1/β5 integrins to mediate the activation of integrin-FAK pathways. While exercise as a lifestyle modification for healthy aging is well recognized, it may present limitations in some aging populations, especially those with disease conditions, including Parkinson's disease. Administration of exogenous irisin or small molecules that increase the expression of endogenous irisin or facilitate its actions are some alternate approaches that can mimic the beneficial actions of exercise. This review discusses the therapeutic potential of irisin in the treatment of neurodegenerative and other aging-associated diseases.