A major limitation in the treatment of manganese-induced parkinsonism is a lack of understanding of the mechanisms that regulate manganese levels in the body.. Somshuvra Mukhopadhyay, MBBS, Ph.D., Associate Professor in the Division of Pharmacology and Toxicology and Hamm Centennial Fellow in Pharmacy, and a team of researchers have published new findings defining the first pathway for homeostatic regulation of manganese in mammalian systems. Identifying these pathways opens up new possible options for preventing or treating manganese-induced parkinsonism and other disorders associated with high manganese exposure.
by Mukhopadhyay last research article, “Upregulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity”, has been published in the Proceedings of the National Academy of Sciences (PNAS), the official journal of the National Academy of Sciences.
“Manganese toxicity is a well-established cause of parkinsonism, but has no cure. By focusing on understanding how our bodies regulate manganese levels, we have been able to uncover a pathway that can potentially be targeted for the treatment of manganese-induced parkinsonism, “says Mukhopadhyay. “In many ways, this study highlights how the findings of basic science can be harnessed for possible therapeutic development. “
Manganese is necessary for life, but at high levels it builds up in the brain and causes parkinsonism. Parkinsonism due to manganese poisoning is seen in people exposed to high levels of metal from occupational (eg welding) or environmental (eg, drinking water) sources, people with breast disease. liver because manganese is excreted by the liver or patients with certain genetic mutations. Mukhopadhyay’s manuscript describes a regulatory pathway through which the body controls manganese levels. Elevations in manganese levels increase the expression of SLC30A10, a protein that excretes manganese, thus providing a pathway to reduce the amount of manganese in the body.
“These findings are a big step forward in our understanding of how the body regulates this biologically essential but potentially toxic metal and identify potential therapeutic approaches to protect against the neurotoxic effects of high manganese exposure,” said the co-author. Dr Donald Smith, professor of microbiology and environmental toxicology at the University of California at Santa Cruz. “Historically, these approaches have involved primary prevention, which is not always possible, or metal chelation therapy, which has not been established to treat manganese poisoning. Therapeutic modulation of the manganese excretion pathway identified in this study represents a new and promising approach to the treatment of manganese poisoning. “Smith is co-inventor of the patent and contributed to the research article with Chunyi liu from the faculty of pharmacy at UT, Thomas Jursa of UC Santa Cruz and Michael aschner from the Albert Einstein College of Medicine.
The article also provides the mechanisms involved in showing that manganese increases SLC30A10 expression by activating a group of proteins called hypoxia-inducible factors, which regulate gene expression. It is important to note that drugs targeting hypoxia-inducible factors, called prolyl hydroxylase inhibitors, have already been developed for the treatment of other diseases, such as kidney anemia. The research team shows that these prolyl hydroxylase inhibitors protect cells and mice against the toxic effects of manganese, suggesting that these drugs could be potential therapeutic agents for the management of manganese-induced parkinsonism in humans.
“This is an important development in advancing technology that will help manage and treat conditions like Parkinson’s disease. We are actively seeking potential partners interested in the development and commercialization of Dr Mukhopadhyay’s technology, ”said Kristen falkenstein, Senior Licensing Specialist in UT Austin’s Technology Commercialization Office.
Mukhopadhyay’s previous research related to manganese, SLC30A10, and parkinsonism has received considerable attention. The paper “The SLC30A10 transporter in the digestive system regulates cerebral manganese under basal conditions while the SLC30A10 brain protects against neurotoxicity” was appointed one of the articles of the year 2019 by the National Institute of Environmental Health Sciences (NIEHS), which is part of the National Institutes of Health (NIH). This too won a 2020 Cooperative Research Excellence Award for the best paper, presented by the Office of the Vice President for Research at the University of Texas at Austin and the University Co-operative Society.
The Mukhopadhyay Lab at the University of Texas at Austin College of Pharmacy focuses on understanding the cell biology of human disease. His two main research projects focus on parkinsonism and metal homeostasis, as well as on intracellular trafficking in Shiga and associated bacterial toxins. This research paper mainly focuses on the first research project. Metals, such as iron, manganese, and copper, are essential for life, but become toxic at high levels and cause serious neurological diseases, such as parkinsonism.