The smoothened agonist SAG reduces mitochondrial dysfunction and neurotoxicity of frataxin-deficient astrocytes
Entity
UAM. Departamento de Biología MolecularPublisher
BMCDate
2022-12-01Citation
10.1186/s12974-022-02442-w
Journal of Neuroinflammation 19.1 (2022): 93
ISSN
1742-2094 (online)DOI
10.1186/s12974-022-02442-wFunded by
This study was supported by research grants from Comunidad Autónoma de Madrid (NEUROMETAB-CM, B2017/BMD-3700) to J.D-N., Spanish Ministerio de Ciencia e Innovación (MICINN, grant PID2019-111338RB-I00) to J.D-N. and A.G-C., Instituto de Salud Carlos III (PI20/00934, co-funded by Fondo Europeo de Desarrollo Regional, FEDER) and Association Française de l’Ataxie de Friedreich (AFAF) to F.L. A.V-A. is supported by a contract from Comunidad Autónoma de Madrid (NEUROMETAB-CM, B2017/BMD-3700)Project
Gobierno de España. PID2019-111338RB-I00; Comunidad de Madrid. B2017/BMD-3700/NEUROMETAB-CMEditor's Version
https://doi.org/10.1186/s12974-022-02442-wSubjects
Cytokine; Mitochondria; Astrocytes; Iron Binding Protein; Biología y Biomedicina / BiologíaRights
© 2022 The Author(s)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
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Google Scholar:Vicente-Acosta, Andrés
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Giménez-Cassina Sendón, Alfredo
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Díaz Nido, Javier
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Loria, Frida
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