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

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.

SUBMITTER: Chen P

PROVIDER: S-EPMC9262395 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Chen Pan P Cheng Hong H Zheng Fuli F Li Shaojun S Bornhorst Julia J Yang Bobo B Lee Kun He KH Ke Tao T Li Yunhui Y Schwerdtle Tanja T Yang Xiaobo X Bowman Aaron B AB Aschner Michael M

Human molecular genetics 20220701 13

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 associ ...[more]

PMID: 35134179

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

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

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