Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity
Rattachement africain : us, ru. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Chronic exposure to high levels of manganese (Mn) leads to manganism, a neurological disorder with similar symptoms to those inherent to Parkinson's disease. However, the underlying mechanisms of this pathological condition have yet to be established. Since the human excitatory amino acid transporter 2 (EAAT2) (glutamate transporter 1 in rodents) is predominantly expressed in astrocytes and its dysregulation is involved in Mn-induced excitotoxic neuronal injury, characterization of the mechanisms that mediate the Mn-induced impairment in EAAT2 function is crucial for the development of novel therapeutics against Mn neurotoxicity. Repressor element 1-silencing transcription factor (REST) exerts protective effects in many neurodegenerative diseases. But the effects of REST on EAAT2 expression and ensuing neuroprotection are unknown. Given that the EAAT2 promoter contains REST binding sites, the present study investigated the role of REST in EAAT2 expression at the transcriptional level in astrocytes and Mn-induced neurotoxicity in an astrocyte-neuron coculture system. The results reveal that astrocytic REST positively regulates EAAT2 expression with the recruitment of an epigenetic modifier, cAMP response element-binding protein-binding protein/p300, to its consensus binding sites in the EAAT2 promoter. Moreover, astrocytic overexpression of REST attenuates Mn-induced reduction in EAAT2 expression, leading to attenuation of glutamate-induced neurotoxicity in the astrocyte-neuron coculture system. Our findings demonstrate that astrocytic REST plays a critical role in protection against Mn-induced neurotoxicity by attenuating Mn-induced EAAT2 repression and the ensuing excitotoxic dopaminergic neuronal injury. This indicates that astrocytic REST could be a potential molecular target for the treatment of Mn toxicity and other neurological disorders associated with EAAT2 dysregulation.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity
- Date Crossref
- 01/12/2021
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Florida Agricultural and Mechanical University pays non établi dans la noticeUniversité ou école supérieure
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Meharry Medical College Department of Biochemistry and Cancer Biology pays non établi dans la noticeUniversité ou école supérieure
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Albert Einstein College of Medicine Department of Molecular Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Sechenov University pays non établi dans la noticeUniversité ou école supérieure
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Florida A&M University - Florida State University College of Engineering Department of Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
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Sechenov First Moscow State Medical University Laboratory of Molecular Nutrition of the Institute for Personalized Medicine pays non établi dans la noticeUniversité ou école supérieure
Florida Agricultural and Mechanical University, Department of Biochemistry and Cancer Biology — Meharry Medical College et Department of Molecular Pharmacology — Albert Einstein College of Medicine, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.