Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

Abstract

Friedreich's ataxia (FA) is a recessive, predominantly neurodegenerative disorder caused in most cases by mutations in the first intron of the frataxin (FXN) gene. This mutation drives the expansion of a homozygous GAA repeat that results in decreased levels of FXN transcription and frataxin protein. Frataxin (Fxn) is a ubiquitous mitochondrial protein involved in iron-sulfur cluster biogenesis, and a decrease in the levels of this protein is responsible for the symptoms observed in the disease. Although the pathological manifestations of FA are mainly observed in neurons of both the central and peripheral nervous system, it is not clear if changes in non-neuronal cells may also contribute to the pathogenesis of FA, as recently suggested for other neurodegenerative disorders. Therefore, the aims of this study were to generate and characterize a cell model of Fxn deficiency in human astrocytes (HAs) and to evaluate the possible involvement of non-cell autonomous processes in FA. To knockdown frataxin in vitro, we transduced HAs with a specific shRNA lentivirus (shRNA37), which produced a decrease in both frataxin mRNA and protein expression, along with mitochondrial superoxide production, and signs of p53-mediated cell cycle arrest and apoptotic cell death. To test for non-cell autonomous interactions we cultured wild-type mouse neurons in the presence of frataxin-deficient astrocyte conditioned medium, which provoked a delay in the maturation of these neurons, a decrease in neurite length and enhanced cell death. Our findings confirm a detrimental effect of frataxin silencing, not only for astrocytes, but also for neuron-glia interactions, underlining the need to take into account the role of non-cell autonomous processes in FA.

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

“…Both dysfunctional frataxin‐deficient neurons and glia are likely to contribute to neuropathology in FA 6, 7. Pathology in FA occurs primarily in the DRG, with significant but independent changes to both the large sensory neurons and surrounding satellite cells, ultimately resulting in neuronal atrophy 5.…”

“…Both dysfunctional frataxin-deficient neurons and glia are likely to contribute to neuropathology in FA. 6,7 Pathology in FA occurs primarily in the DRG, with significant but independent changes to both the large sensory neurons and surrounding satellite cells, ultimately resulting in neuronal atrophy. 5 Replacement of these dysfunctional cell types within the DRG of transplanted mice, which under normal conditions provide bidirectional trophic support to one another, 5 may improve the survival of DRG neurons.…”

“…Neuronal atrophy and dysfunctional glia are both thought to contribute to neuropathology in FA 3, 5, 6, 7. Despite advances in understanding of the disease, current therapeutics show little ability to protect nervous tissue and no capacity to promote repair.…”

“…3,4 Neuronal atrophy and dysfunctional glia are both thought to contribute to neuropathology in FA. 3,[5][6][7] Despite advances in understanding of the disease, current therapeutics show little ability to protect nervous tissue and no capacity to promote repair. Adult stem cell populations, notably those that reside within the bone marrow (BM), have been shown both to provide neurotrophic support and to contribute to neuronal/glial cell types in the brain through processes likely involving cellular fusion.…”

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

“…These common genes, however, were uniquely enriched for genes involved in the regulation of apoptosis. Involvement of apoptotic mechanisms has been previously reported in FRDA cells (53,70,72,87,88). This suggests that to overcome the pitfalls of studies centered on iPSC-derived cell models, both multiple cell lines and isogenic lines are necessary.…”