The smoothened agonist SAG reduces mitochondrial dysfunction and neurotoxicity of frataxin-deficient astrocytes.

Abstract

BACKGROUND:

Friedreich's ataxia is a rare hereditary neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Similar to other neurodegenerative pathologies, previous studies suggested that astrocytes might contribute to the progression of the disease. 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.

RESULTS:

We observed loss of cell viability, mitochondrial alterations, increased autophagy and lipid accumulation in cultured astrocytes upon frataxin depletion. Besides, frataxin-deficient cells show higher expression of several A1-reactivity markers and release of pro-inflammatory cytokines. Interestingly, most of these defects were prevented by chronically treating the cells with the smoothened agonist SAG. 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. However, when frataxin-deficient astrocytes were chronically treated with SAG, we did not observe these alterations in neurons.

CONCLUSIONS:

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.

• Authors: Andrés Vicente-Acosta, Alfredo Giménez-Cassina, Javier Díaz-Nido, Frida Loria
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 19 Issue 1 Pg. 93 (Apr 12 2022) ISSN: 1742-2094 [Electronic] England
• PMID: 35413853 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Iron-Binding Proteins
• frataxin

Topics

• Astrocytes (metabolism)
• Friedreich Ataxia (drug therapy, genetics, pathology)
• Humans
• Iron-Binding Proteins
• Mitochondria
• Neurodegenerative Diseases (metabolism)
• Neurotoxicity Syndromes (metabolism)