Recent research suggests that neuroinflammation could be a significant factor in the pathophysiology of Friedreich ataxia (FA), a disorder for which there is no cure. Previously underestimated, neuroinflammation, particularly in the cerebellum and spinal cord, is now recognized to have crucial implications for the disease’s mechanisms and potential treatments.

“The absence of an effective treatment for FA is mainly due to underestimating some processes influencing denervation-induced muscle atrophy. Among these mechanisms, the contribution of neuroinflammation to the pathology has been largely neglected, possibly missing out on relevant diagnostic, prognostic, and therapeutic targets of the disease,” wrote Savina Apolloni and colleagues in a review article published in The International Journal of Molecular Sciences.

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Although the exact connection between neuroinflammation and FA’s onset remains unclear, evidence suggests that glial activation triggered by neuronal loss and FXN knockdown contributes to the development of a cytotoxic environment and neuroinflammation. This suggests that FA involves noncell-autonomous mechanisms, with FXN influencing glial activity and causing neuronal damage.

Researchers from the Université Libre de Bruxelles in Belgium, found several differentially expressed proteins (DEPs) in the cerebrospinal fluid of patients with FA that pointed to neurodegeneration and neuroinflammation, indicating that these processes could be key factors in FA’s progression and potential treatment strategies.

“Neurodegeneration and neuroinflammation are processes that may respond to treatment, so at least some of these DEPs may turn out to be treatment response biomarkers in addition to diagnostic biomarkers,” the researchers wrote in Frontiers in Neuroscience.

Although several neuroinflammation-related pathways are altered in microglia, astrocytes, and myelinating glial cells in FA, a comprehensive understanding of their role is still lacking.

As scientists delve into the intricate relationship between genetic factors, glial cells, and neuroinflammation in FA, new avenues may emerge for targeted therapies and interventions.

Microglia in FA

Early investigations reported the loss of juxtaneuronal ferritin-containing oligodendroglia and ferritin immunoreactivity in microglia and astrocytes in the dentate nucleus of patients with FA. These alterations were accompanied by neuronal atrophy and an unusual proliferation of synaptic terminals called “grumose degeneration,” indicating possible issues with iron metabolism in the terminals of corticonuclear fibers.

The observed grumose degeneration in FA appeared to trigger a substantial response among microglial cells, involving the participation of superoxide dismutase type 1, an antioxidant enzyme. This suggested that the iron accumulation characteristic of FA might incite a defensive reaction in glial cells, aimed at safeguarding neurons from oxidative harm.

Moreover, the atrophic dentate nucleus of patients with FA exhibited abundant and hypertrophic ferritin-positive microglia, indicating an overall active glial state. Imaging studies have corroborated these observations by confirming widespread reactive gliosis across the brains of patients. All regions implicated in FA neuropathology, including the dentate nuclei, brainstem, superior cerebellar peduncles, and cerebellar cortex, showed increased glial activation compared to control subjects.

The increased microgliosis in FA brains may stem from an increased need to eliminate harmful substances and defunct neurons, potentially releasing accumulated iron through phagocytosis.

Additionally, insights gleaned from animal models have indicated that microglial activation is more pronounced in FA mice than their healthy counterparts when exposed to the inflammatory stimulus lipopolysaccharide (LPS). Analysis of cerebellar microglia in FA mice also suggested heightened activation compared to their healthy counterparts.

FA mice exhibited oxidative damage and changes in DNA repair proteins (eg, poly [ADP-ribose] polymerase 1 [PARP-1]) within cerebellar microglia. Administration of PARP-1 inhibitor, PJ34, ameliorated these anomalies, underscoring the potential of microglial PARP-1 as a therapeutic target in FA.

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Notably, transplantation of healthy hematopoietic stem and progenitor cells resulted in improved muscle weakness and locomotor deficits in FA mice. These transplanted cells differentiated into microglia in the brain and spinal cord, and into macrophages in other tissues, suggesting that replacing FXN-deficient microglia with healthy ones could contribute to neurological improvements.

In the cerebella of FA mice, inducible cyclooxygenase 2 expression and activity were heightened, accompanied by increased transcription factors activator protein 1 and cAMP response element-binding protein. These changes pointed to a plausible connection between FXN deficiency, neuroinflammation, and the generation of reactive oxygen species. Furthermore, FXN deficiency exacerbated microglial reactivity following LPS treatment, highlighting an increased vulnerability to inflammation when compared to healthy mice.

Astrocytes in FA

Astrocytes have emerged as key players in the development of various forms of ataxias. In FA, cerebellar tissues of patients showed marked astrogliosis in the dentate nucleus, with ferritin-positive astrocytes lining vessel walls. Additionally, postmortem examinations reveal central nervous system-derived astroglia infiltrating the dorsal roots.

The loss of the FXN gene in FA doesn’t solely affect neurons; it also disrupts normal astroglial function. FXN-deficient astrocytes exhibited compromised mitochondrial integrity, oxidative stress, altered molecular secretion, and hindered neuron development. Altered mitochondrial iron regulation due to FXN deficiency contributed to oxidative stress and the production of superoxide, contributing to the noncell-autonomous effects observed in FA.

Astrocytes differentiated from neural stem cells of an FA mouse model exhibited reduced aconitase activity, a bioenergetic dysfunction marker common in neurodegenerative diseases. FXN-deficient astrocytes also showed lower levels of antioxidant enzymes and DNA mismatch repair enzymes, increasing their susceptibility to oxidative stress.

Further studies involving mouse models demonstrated that developing cerebellar astrocytes were especially vulnerable to FXN deficiency. Deleting FXN in astrocytes during development led to severe ataxia and growth impairments, while the same deletion in mature astrocytes did not cause apparent neurological issues. Neuroinflammation and astrocytosis were observed in FXN-deficient mice, further emphasizing the role of astrocytes in FA progression.

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Targeting astrocytes has proved beneficial in several models. For instance, treatment with insulin-like growth factor 1 rescued astrocyte-associated defects and atrophy, improving motor performance and survival. Similarly, treatment with granulocyte-colony stimulating factor and stem cell factor reduced astrocytosis and inflammatory cell infiltration, slowing disease progression. Targeting Sonic Hedgehog rescued mitochondrial dysfunction and neurotoxicity in FXN-deficient astrocytes.

In Drosophila melanogaster, FXN knockdown in glia led to locomotion issues, cellular degeneration, and oxidative stress. Expressing Glaz, a homolog of apolipoprotein D, in FXN-deficient glia improved outcomes. Genetic studies identified mitofusin (Marf), involved in mitochondrial function, as a critical factor. Marf downregulation rescued FXN silencing effects, demonstrating the complexity of astrocyte-neuron interactions in FA. Overall, astrocyte activation seems to trigger a detrimental cycle, worsening neuronal dysfunctions in FA.

Myelinating Glial Cells in FA

Myelinating glial cells, including oligodendroglia and Schwann cells, have also been implicated in FA, being highly susceptible to FXN deficiency. In patients with FA, the dentate nucleus contains mainly ferritin-expressing oligodendrocytes. However, as the disease progresses and neurons undergo atrophy, these cells vanish, being replaced by ferritin-positive microglia.

Reducing FXN levels triggered significant declines in the proliferation of both oligodendrocytes and Schwann cells through the activation of inflammatory pathways. In FXN-deficient Schwann cells, microarray analysis revealed a decrease in antioxidant genes coupled with a notorious rise in inflammatory cytokines. This suggests these inflammatory cytokines may contribute to neuron loss in the dorsal root ganglia.

Collectively, this evidence implies that the presence of mutant FXN in glial cells could act as a trigger, leading to their reprogramming and functional impairment, ultimately contributing to the degeneration of neighboring neurons.


Apolloni S, Milani M, D’Ambrosi N. Neuroinflammation in Friedreich’s Ataxia. Int J Mol Sci. Published online June 4, 2022. doi:10.3390/ijms23116297

Imbault V, Dionisi C, Naeije G, Communi D, Pandolfo M. Cerebrospinal fluid proteomics in Friedreich ataxia reveals markers of neurodegeneration and neuroinflammation. Front Neurosci. Published online July 13, 2022. doi:10.3389/fnins.2022.885313.