Streptozotocin-Induced Astrocyte Mitochondrial Dysfunction Is Ameliorated by FTO Inhibitor MO-I-500
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- Alzheimer’s disease, MO-I-500, Streptozotocin, astrocytes, m6A demethylase FTO, mitochondria,
- MeSH
- Adenosine MeSH
- Astrocytes * MeSH
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO * MeSH
- Humans MeSH
- Mitochondria MeSH
- Streptozocin toxicity MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Adenosine MeSH
- FTO protein, human MeSH Browser
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO * MeSH
- Streptozocin MeSH
The pathogenesis of Alzheimer's disease (AD), the most prevalent form of dementia, remains unclear. Over the past few years, evidence has accumulated indicating that perturbed cerebral bioenergetics and neuroinflammation may compromise cognitive functions and precedes the onset of AD and that impaired function of glial cells can likely contribute to the development of the disease. Recently, N6-methyladenosine (m6A) modification of RNA has been implicated in the regulation of different processes in the brain and to play a potential role in neurodegeneration. In the present study, we investigated the potential role of the m6A machinery enzymes in a streptozotocin (STZ) model of AD in human astrocytoma CCF-STTG1 cells. We observed that STZ-treated astrocytes expressed significantly higher levels of m6A demethylase fat mass and obesity-associated protein (FTO) and m6A reader YTHDF1 (YTH domain-containing family protein 1). Our experiments revealed that MO-I-500, a novel pharmacological inhibitor of FTO, can strongly reduce the adverse effects of STZ. Inhibition of FTO enhanced the survival of cells exposed to STZ and suppressed oxidative stress, apoptosis, elevated expression of glial fibrillary acidic protein, mitochondrial dysfunction, and bioenergetic disturbances induced by this compound. Overall, the results of this study indicate that perturbed m6A signaling may be contributing to AD pathogenesis, likely by compromising astrocyte bioenergetics.
Department of Physiology Faculty of Science Charles University 128 00 Prague Czech Republic
International Clinical Research Center St Anne's University Hospital Brno 656 91 Brno Czech Republic
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