Does PGC1α/FNDC5/BDNF Elicit the Beneficial Effects of Exercise on Neurodegenerative Disorders?

Neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases have high prevalence among the elderly. Many strategies have been established to alleviate the symptoms experienced by affected individuals. Recent studies have shown that exercise helps patients with neurological disorders to regain lost physical abilities. PGC1 alpha/FNDC5/BDNF has emerged recently as a critical pathway for neuroprotection. PGC1 alpha is a highly conserved co-activator of transcription factors that preserves and protects neurons against destruction. PGC1 alpha regulates FNDC5 and its processed and secreted peptide Irisin, which has been proposed to play a critical role in energy expenditure and to promote neural differentiation of mouse embryonic stem cells. FNDC5 may also increase the expression of the neurotrophic factor BDNF, a neuroprotective agent, in the hippocampus. BDNF is secreted from hippocampus, amygdala, cerebral cortex and hypothalamus neurons and initiates intracellular signaling pathways through TrkB receptors. These pathways have positive feedback on CREB activities and lead to enhancement in PGC1 alpha expression in neurons. Therefore, FNDC5 could behave as a key regulator in neuronal survival and development. This review presents recent findings on the PGC1 alpha/FNDC5/BDNF pathway and its role in neuroprotection, and discusses the controversial promise of irisin as a mediator of the positive benefits of exercise.