Homocysteine-potentiated Kelch-like ECH-associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of β-catenin.
KEAP1
homocysteine
methylation
senescence
β-catenin
Journal
The European journal of neuroscience
ISSN: 1460-9568
Titre abrégé: Eur J Neurosci
Pays: France
ID NLM: 8918110
Informations de publication
Date de publication:
19 Mar 2024
19 Mar 2024
Historique:
revised:
24
12
2023
received:
04
05
2023
accepted:
25
02
2024
medline:
19
3
2024
pubmed:
19
3
2024
entrez:
19
3
2024
Statut:
aheadofprint
Résumé
Elevated serum homocysteine (Hcy) level is a risk factor for Alzheimer's disease (AD) and accelerates cell aging. However, the mechanism by which Hcy induces neuronal senescence remains largely unknown. In this study, we observed that Hcy significantly promoted senescence in neuroblastoma 2a (N2a) cells with elevated β-catenin and Kelch-like ECH-associated protein 1 (KEAP1) levels. Intriguingly, Hcy promoted the interaction between KEAP1 and the Wilms tumor gene on the X chromosome (WTX) while hampering the β-catenin-WTX interaction. Mechanistically, Hcy attenuated the methylation level of the KEAP1 promoter CpG island and activated KEAP1 transcription. However, a slow degradation rate rather than transcriptional activation contributed to the high level of β-catenin. Hcy-upregulated KEAP1 competed with β-catenin to bind to WTX. Knockdown of both β-catenin and KEAP1 attenuated Hcy-induced senescence in N2a cells. Our data highlight a crucial role of the KEAP1-β-catenin pathway in Hcy-induced neuronal-like senescence and uncover a promising target for AD treatment.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The Intramural Research Program of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology
ID : 2023LYYYGZRP0004
Organisme : National Key Research and Development Program of China
Organisme : National Basic Research Development Program of the Ministry of Science and Technology of China
ID : 2016YFC1305800
Organisme : National Natural Science Foundation of China
ID : 31730035
Organisme : National Natural Science Foundation of China
ID : 91632305
Organisme : National Natural Science Foundation of China
ID : 9194920041
Informations de copyright
© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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