BTBD9 attenuates manganese-induced oxidative stress and neurotoxicity by regulating insulin growth factor signaling
Pan Chen1, Hong Cheng2, Fuli Zheng1
1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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.
Insights
High manganese (Mn) exposure may increase restless legs syndrome (RLS) risk by reducing BTBD9 levels, which normally protect against Mn-induced neurotoxicity via the insulin signaling pathway.
Area of Science:
- Neuroscience
- Environmental Health
- Genetics
Background:
- Manganese (Mn) is essential but toxic in excess, potentially causing dopaminergic neurotoxicity.
- Restless Legs Syndrome (RLS) is a common neurological disorder with unknown causes.
- BTBD9 is a known genetic risk factor for RLS.
Purpose of the Study:
- To investigate the role of manganese (Mn) in regulating the RLS genetic risk factor BTBD9.
- To characterize BTBD9's function in mitigating Mn-induced oxidative stress and dopaminergic neurotoxicity.
Main Methods:
- Correlated blood Mn levels with BTBD9 mRNA in human subjects.
- Exposed A549 cells to Mn to assess BTBD9 protein levels.
- Utilized Caenorhabditis elegans models with altered hpo-9 (BTBD9 homolog) expression to study Mn effects on oxidative stress, mitochondrial function, dopamine levels, and neuronal morphology.
- Investigated the involvement of the FOXO and insulin/IGF signaling pathways.
Main Results:
- High blood Mn levels correlated with decreased BTBD9 mRNA in humans.
- Mn exposure reduced BTBD9 protein in A549 cells.
- Loss of hpo-9 in C. elegans increased susceptibility to Mn-induced oxidative stress, mitochondrial dysfunction, and dopaminergic deficits.
- hpo-9 overexpression restored normal function, dependent on FOXO.
- hpo-9 expression increased FOXO and decreased Akt levels.
Conclusions:
- Elevated manganese exposure may be an environmental risk factor for Restless Legs Syndrome.
- BTBD9 plays a protective role against Mn-induced neurotoxicity and oxidative stress.
- BTBD9 exerts its protective effects through the regulation of the insulin/insulin-like growth factor signaling pathway.
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