2. Academic Validation
  3. 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

  • Sci Total Environ. 2023 Apr 16;881:163429. doi: 10.1016/j.scitotenv.2023.163429.
Chunyan Zheng 1,  Guangxia Yu 2,  Qianqian Su 1,  Lingyan Wu 1,  Jianping Tang 1,  Xinpei Lin 1,  Yao Chen 1,  Zhenkun Guo 1,  Fuli Zheng 2,  Hong Zheng 3,  Liqiong Lin 3,  Ying Tang 4,  Siying Wu 5,  Huangyuan Li 6
Affiliations

Affiliations

  • 1 Fujian Key Lab of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China.
  • 2 Fujian Key Lab of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Key Lab of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, China.
  • 3 Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou 350007, China.
  • 4 Fujian Center for Prevention and Control Occupational Diseases and Chemical Poisoning, Fuzhou 350125, China.
  • 5 Fujian Key Lab of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Key Lab of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, China. Electronic address: [email protected].
  • 6 Fujian Key Lab of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou 350122, China; Key Lab of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou 350122, China. Electronic address: [email protected].
PMID: 37072102 DOI: 10.1016/j.scitotenv.2023.163429
Abstract

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 m6A methylation alteration is involved in cobalt-induced neurodegenerative damage, such as in AD. However, the role of m6A 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 m6A 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 m6A-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.

Keywords

ALKBH5; Cobalt; Epigenetics; Neurodegeneration; Neurotoxicity; m(6)A.

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