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.

Transactivation Response DNA-Binding Protein of 43 (TDP-43) and Glial Cell Roles in Neurological Disorders

“…FRDA is a genetic neurodegenerative disorder that is commonly associated with cardiomyopathy [104]. Neurodegenerative manifestations can arise early in the course and present with unsteady posture, frequent falls, and difficulty walking.…”

“…Neurodegenerative manifestations can arise early in the course and present with unsteady posture, frequent falls, and difficulty walking. Some individuals can develop ataxia, loss of speech, and scoliosis [104]. The disease is caused by mutations in the FXN gene that codes for a mitochondrial protein called frataxin [104].…”

“…Some individuals can develop ataxia, loss of speech, and scoliosis [104]. The disease is caused by mutations in the FXN gene that codes for a mitochondrial protein called frataxin [104]. The primary role of this protein is to regulate iron hemostasis and iron-sulfur cluster production.…”

“…Glial cell mechanisms have been well understood in this disease and multiple pathways take place, leaving a detrimental impact. There is mitochondrial disruption, active iron form accumulation due to the Fenton and Haber−Weiss reactions, and production of hydroxyl radicals that ultimately exacerbate glial cell loss [104]. The primary producers of ROS within the CNS are microglial cells via the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) [104].…”

Perspectives on current models of Friedreich’s ataxia

“…Neurological symptoms include progressive ataxia of gait and limbs, increased muscle tone, decrease in or loss of position sense and tendon reflexes, difficulty swallowing, and dysarthria ( Filla et al, 1990 ; Parkinson et al, 2013 ). Additionally, neuroinflammation and upregulation of glial activation in the cerebellum and brainstem are observed ( Apolloni et al, 2022 ; Khan et al, 2022 ). Non-neurological symptoms include hypertrophic cardiomyopathy, glucose intolerance, and diabetes mellitus ( Campuzano et al, 1996 ; Gottesfeld, 2019 ).…”