In up to 95% of cases, FRDA is caused by an expansion of a guanine–adenine–adenine (GAA) triplet located in the first intron of the FXN gene, causing a significant reduction in the transcription levels of the mitochondrial protein frataxin (FXN). The progressive cerebellar damage leads to loss of movement coordination and equilibrium in FRDA patients.
It is characterized by a developmental hypoplasia affecting the spinal cord and medulla, and a neurodegenerative process mainly affecting the cerebellum. Our results demonstrate that the pharmacological activation of the SHH pathway could be used as a target to modulate astrocyte reactivity and neuron–glia interactions to prevent neurodegeneration in Friedreich’s ataxia.įriedreich´s ataxia (FRDA) is a neurodegenerative disease, with an autosomal recessive inheritance pattern, for which there is still no cure. However, when frataxin-deficient astrocytes were chronically treated with SAG, we did not observe these alterations in neurons. Furthermore, in vitro culture of neurons with conditioned medium from frataxin-deficient astrocytes results in a reduction of neuronal survival, neurite length and synapse formation. Interestingly, most of these defects were prevented by chronically treating the cells with the smoothened agonist SAG. Besides, frataxin-deficient cells show higher expression of several A1-reactivity markers and release of pro-inflammatory cytokines. We observed loss of cell viability, mitochondrial alterations, increased autophagy and lipid accumulation in cultured astrocytes upon frataxin depletion. To fully understand the mechanisms underlying neurodegeneration in Friedreich’s ataxia, we investigated the reactivity status and functioning of cultured human astrocytes after frataxin depletion using an RNA interference-based approach and tested the effect of pharmacologically modulating the SHH pathway as a novel neuroprotective strategy.
Similar to other neurodegenerative pathologies, previous studies suggested that astrocytes might contribute to the progression of the disease. Friedreich’s ataxia is a rare hereditary neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin.