2. Academic Validation
  3. BTBD9 attenuates manganese-induced oxidative stress and neurotoxicity by regulating insulin growth factor signaling pathway

BTBD9 attenuates manganese-induced oxidative stress and neurotoxicity by regulating insulin growth factor signaling pathway

  • Hum Mol Genet. 2022 Jul 7;31(13):2207-2222. doi: 10.1093/hmg/ddac025.
Pan Chen 1,  Hong Cheng 2,  Fuli Zheng 1,  Shaojun Li 1 2,  Julia Bornhorst 3,  Bobo Yang 1,  Kun He Lee 1,  Tao Ke 1,  Yunhui Li 1 4,  Tanja Schwerdtle 5 6,  Xiaobo Yang 2 7,  Aaron B Bowman 8,  Michael Aschner 1
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 2 Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning 53021, China.
  • 3 Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal 42119, Germany.
  • 4 Key Laboratory of Environmental Medicine Engineering Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu 210000, China.
  • 5 Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal 14558, Germany.
  • 6 TraceAge-DFG Research Group on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena 14558, Germany.
  • 7 Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou 545026, China.
  • 8 School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
PMID: 35134179 DOI: 10.1093/hmg/ddac025
Abstract

Manganese (Mn) is an essential mineral, but excess exposure can cause dopaminergic neurotoxicity. Restless legs syndrome (RLS) is a common neurological disorder, but the etiology and pathology remain largely unknown. The purpose of this study was to identify the role of Mn in the regulation of an RLS genetic risk factor BTBD9, characterize the function of BTBD9 in Mn-induced oxidative stress and dopaminergic neuronal dysfunction. We found that human subjects with high blood Mn levels were associated with decreased BTBD9 mRNA levels, when compared with subjects with low blood Mn levels. In A549 cells, Mn exposure decreased BTBD9 protein levels. In Caenorhabditis elegans, loss of hpo-9 (BTBD9 homolog) resulted in more susceptibility to Mn-induced oxidative stress and mitochondrial dysfunction, as well as decreased dopamine levels and alternations of dopaminergic neuronal morphology and behavior. Overexpression of hpo-9 in mutant Animals restored these defects and the protection was eliminated by mutation of the forkhead box O (FOXO). In addition, expression of hpo-9 upregulated FOXO protein levels and decreased protein kinase B levels. These results suggest that elevated Mn exposure might be an environmental risk factor for RLS. Furthermore, BTBD9 functions to alleviate Mn-induced oxidative stress and neurotoxicity via regulation of Insulin/insulin-like growth factor signaling pathway.

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