Promising therapy for manganese-induced neurological disorder
NIEHS-funded researchers discovered how manganese (Mn) is regulated in the body, pointing to a promising therapy for Mn-induced neurological disorders, which resemble Parkinson’s disease. Until now, treatments have been hindered by a limited understanding of the mechanisms controlling Mn in the body.
The researchers exposed mice to Mn in drinking water from birth to eight weeks of age. They then measured expression of SLC30A10, a protein that plays an important role in eliminating Mn from the body. Compared with unexposed controls, the mice given Mn had increased SLC30A10 levels in the intestines and liver, which are responsible for excreting Mn. In human liver cell cultures genetically modified to block SLC30A10, there were higher levels of Mn and cell death compared with controls, suggesting that upregulation of SLC30A10 is critical to reduce Mn in the body and protect against toxicity.
Mechanistic studies in human liver cell cultures revealed that Mn exposure increased levels of proteins called hypoxia inducible factors (HIFs), and that HIFs were required for SLC30A10 upregulation. Further examination showed that Mn increased HIFs by blocking proteins called prolyl hydroxylases, which are necessary for degrading HIFs.
To examine potential therapies for Mn toxicity, the researchers treated Mn-exposed liver cells and mice with drugs that block prolyl hydroxylases. In cells, drug treatment increased HIF levels, enhanced SLC30A10 expression, and reduced cellular Mn levels. In mice, drug treatment increased SLC30A10 in the intestine, reduced Mn in the brain, and improved neurobehavioral outcomes, compared with mice not given the drug.
Citation: Liu C, Jursa T, Aschner M, Smith DR, Mukhopadhyay S. 2021. Up-regulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity. Proc Natl Acad Sci USA 118(35):e2107673118.