Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes

Abstract

Friedreichs ataxia (FRDA) is a neurodegenerative disorder characterized by severe neurological signs affecting both the peripheral and central nervous system, caused by reduced levels of the frataxin protein (FXN). While several studies highlight cellular dysfunctions in neurons and various other cell types, there is limited information on the effects of FXN depletion in astrocytes and on the potential non-cell autonomous mechanisms affecting neurons in FRDA. In this study, we generated a model of FRDA cerebellar astrocytes to unveil phenotypic alterations that might contribute to cerebellar atrophy and the degeneration of glutamatergic neurons observed in cerebellar dentate nuclei. We treated primary cerebellar astrocytes with an RNA interference-based approach, to achieve a reduction of FXN comparable to that observed in patients. These FRDA-like astrocytes display some typical features of the disease, such as an increase of oxidative stress, as well as specific functional alterations. Notably, cerebellar astrocytes deplete their reduced glutathione content, becoming more susceptible to oxidative insults. Moreover, FRDA-like astrocytes exhibit alterations of calcium homeostasis, with a reduction in calcium content in the intracellular stores and a corresponding change of calcium responses to purinergic stimuli. Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, which can interfere with their physiological and complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators and bioactive molecules in a calcium-dependent manner could impact neuronal function and contribute to neurodegeneration.