Neuroinflammation in Friedreich's Ataxia

Abstract

Friedreich's ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron-sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms. Iron accumulation, mitochondria dysfunction, and reactive species overproduction, mechanisms identified as etiopathogenic in neurons in FRDA, can similarly affect glial cells, leading them to assume phenotypes that can concur to and exacerbate neuron loss. Recent findings obtained in FRDA patients and cellular and animal models of the disease have suggested that neuroinflammation can accompany and contribute to the neuropathology. In this review article, we discuss evidence about the involvement of neuroinflammatory-related mechanisms in models of FRDA and provide clues for the modulation of glial-related mechanisms as a possible strategy to improve disease features.

Keywords: astrocytes; frataxin; iron; microglia; neurons.

Figure 1

Neuroinflammation-related pathways altered in Friedreich’s ataxia (FRDA). Cerebellum, spinal cord, and dorsal root ganglia are three of the principal nervous system organs involved in the pathogenesis of FRDA. The genetically decreased expression of frataxin (FXN) leads to the disturbance of the metabolism of iron with the consequent iron increase in reactive microglia and astrocytes, together with mitochondria dysfunctions. FRDA microglia show an increase in oxidative damage, and the DNA repair proteins MUTYH and PARP-1, reactive oxygen species (ROS), activator protein 1 (AP1), and cAMP response element-binding protein (CREB), known to drive cyclooxygenase 2 (COX2) expression. In FRDA astrocytes, the depletion of FXN leads to an increase in ROS, COX2, MIP-1α, IL-6, p53, p21, and activated caspase-3 (CASP3), and to a decrease in mitochondrial aconitase, Pgc-1α, Sod2, and glutathione peroxidase 1 (GPX1) with a significant reduction in the expression of several MMR genes. Finally, FXN deficiency causes an increase in IL-6, IL-1b, and TNF-a in dysfunctional Schwann cells. N, nucleus; C, cytosol; ECM, extracellular matrix.