2. Academic Validation
  3. Homocysteine-potentiated Kelch-like ECH-associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of β-catenin

Homocysteine-potentiated Kelch-like ECH-associated protein 1 promotes senescence of neuroblastoma 2a cells via inhibiting ubiquitination of β-catenin

  • Eur J Neurosci. 2024 Mar 19. doi: 10.1111/ejn.16318.
Yao Zhang 1,  Jia-Zhao Xie 2 3,  Yan-Li Jiang 4,  Shao-Juan Yang 4,  Hui Wei 2,  Ying Yang 2,  Jian-Zhi Wang 2 5
Affiliations

Affiliations

  • 1 Endocrine Department of Liyuan Hospital; Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Precision Medical Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
  • 4 Endocrine Department of Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
PMID: 38501537 DOI: 10.1111/ejn.16318
Abstract

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.

Keywords

KEAP1; homocysteine; methylation; senescence; β-catenin.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z