The deficiency of N6-methyladenosine demethylase ALKBH5 enhances the neurodegenerative damage induced by cobalt
The deficiency of N6-methyladenosine demethylase ALKBH5 enhances the neurodegenerative damage induced by cobalt
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DOI：
10.1016/j.scitotenv.2023.163429
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发表时间：
2023
影响因子：
9.8
通讯作者：
Huangyuan Li
中科院分区：
文献类型：
--
作者：
Chunyan Zheng;Guangxia Yu;Qianqian Su;Lingyan Wu;Jianping Tang;Xinpei Lin;Yao Chen;Zhenkun Guo;Fuli Zheng;Hong Zheng;Liqiong Lin;Ying Tang;Siying Wu;Huangyuan Li
Cobalt exposure, even at low concentrations, induces neurodegenerative damage, such as Alzheimer's disease (AD)..The specific underlying mechanisms remain unclear. Our previous study demonstrated that m6.A methylation alteration is involved in cobalt-induced neurodegenerative damage, such as in AD. However, the role of m6.A RNA methylation and its underlying mechanisms are poorly understood. In this study, both epidemiological and laboratory studies.showed that cobalt exposure could downregulate the expression of the m6.A demethylase ALKBH5, suggesting a key.role for ALKBH5. Moreover, Methylated RNA immunoprecipitation and sequencing (MeRIP-seq) analysis revealed.that ALKBH5 deficiency is associated with neurodegenerative diseases. KEGG pathway and Gene ontology analyses.further revealed that the differentially m6.A-modified genes resulting from ALKBH5 downregulation and cobalt exposure were aggregated in the pathways of proliferation, apoptosis, and autophagy. Subsequently, ALKBH5 deficiency.was shown to exacerbate cell viability decline, motivate cell apoptosis and attenuate cell autophagy induced by cobalt.with experimental techniques of gene overexpression/inhibition. In addition, morphological changes in neurons and.the expression of AD-related proteins, such as APP, P-Tau, and Tau, in the cerebral hippocampus of wild-type and ALKBH5 knockout mice after chronic cobalt exposure were also investigated. Both in vitro and in vivo results showed.that lower expression of ALKBH5 aggravated cobalt-induced neurodegenerative damage. These results suggest that.ALKBH5, as an epigenetic regulator, could be a potential target for alleviating cobalt-induced neurodegenerative damage. In addition, we propose a novel strategy for the prevention and treatment of environmental toxicant-related neurodegeneration from an epigenetic perspective.
