FNDC5/Irisin System in Neuroinflammation and Neurodegenerative Diseases: Update and Novel Perspective

Abstract

Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha PGC1α control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous system functioning, particularly the hippocampus, resulting in amelioration of cognition impairments. Recently, FNDC5/irisin detection in hippocampal neurons and the presence of irisin in the cerebrospinal fluid opened a new intriguing chapter in irisin history. Interestingly, in the hippocampus of mice, exercise increases FNDC5 levels and upregulates brain-derived neurotrophic factor (BDNF) expression. BDNF, displaying neuroprotection and anti-inflammatory effects, is mainly produced by microglia and astrocytes. In this review, we discuss how these glial cells can morphologically and functionally switch during neuroinflammation by modulating the expression of a plethora of neuroprotective or neurotoxic factors. We also focus on studies investigating the irisin role in neurodegenerative diseases (ND). The emerging involvement of irisin as a mediator of the multiple positive effects of exercise on the brain needs further studies to better deepen this issue and the potential use in therapeutic approaches for neuroinflammation and ND.

Keywords: FNDC5; irisin; neurodegeneration; neuroinflammation.

Figure 1

Mechanism of irisin release into the blood. Schematic structure of irisin precursor fibronectin type III domain-containing protein 5 (FNDC5) and its amino acid sequence (upper panel). FNDC5 cleavage, by a yet unknown enzyme at levels of the extracellular domain, gives rise to the release of irisin into the blood, a peptide consisting of a sequence of 112 amino acids (lower panel). Abbreviations: SP, signal peptide; H, hydrophobic domain; C, cytoplasmic domain. Symbols: ? indicates the unknown enzyme.

Figure 2

Scheme of fibronectin type III domain-containing protein 5 (FNDC5)/irisin system in the protection against neuroinflammation and neurodegeneration. Black arrows indicate irisin sources. Dotted green lines show the beneficial irisin effects. Green arrows indicate: ↑ increase and ↓ reduction.