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

Abstract

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. PGC1α/FNDC5/BDNF has emerged recently as a critical pathway for neuroprotection. PGC1α is a highly conserved co-activator of transcription factors that preserves and protects neurons against destruction. PGC1α 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 PGC1α expression in neurons. Therefore, FNDC5 could behave as a key regulator in neuronal survival and development. This review presents recent findings on the PGC1α/FNDC5/BDNF pathway and its role in neuroprotection, and discusses the controversial promise of irisin as a mediator of the positive benefits of exercise.

BDNF as a Promising Therapeutic Agent in Parkinson’s Disease

“…As previously mentioned, the key element of neurotrophin-related neuroprotection is the IP3/Akt kinase pathway [186]. Data were also presented which indicate that physical activity may be neuroprotective by activating the PGC1a/FNDC5/BDNF/ERK1/2 pathway [187,188]. In addition, exercises increase transcription of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), a protein that regulates mitochondrial biogenesis, which, in complex with estrogen-related receptor alpha, can stimulate the expression of myokine, the fibronectin type III domain-containing protein 5 (FNDC5) in the brain [187].…”

Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation

“…The inhibition of Na + –K + ATPase transporter involved in maintenance of resting potential of cell membrane, has led to membrane depolarization [63], as observed in the brain of rats by Kumari and colleagues [64]. Depolarization of cellular membrane can cause Ca 2+ ions entry into the cell and finally apoptosis through activation of N -methyl- d -aspartate (NMDA) receptors [63]. Wu et al observed an increase in expression of bax and a decrease in expression of bcl - 2 in the PC12 cells exposed with IONPs [55].…”

Lactate and BDNF: Key Mediators of Exercise Induced Neuroplasticity?

“…Activation of TrkB triggers intracellular signal cascades such as mitogen-activated protein kinase (MAPK), phospholipase C-γ (PLCγ) or phosphatidylinositol-3-kinase (PI 3 K) pathways [29]. Additionally, TrkB activation can also increase the expression of the peroxisome proliferator-activated receptor γ co-activator α (PGC1α) which in turn increases BDNF expression in neurons via the PGC1α/FNDC5/BDNF pathway [30,31].…”