Research Provides Further Insight into Causes of Manganese-Induced Parkinsonism

By Nick Nobel
September 7, 2021
A man smiling in a research lab.

A major limitation in treating manganese-induced parkinsonism is a lack of understanding of the mechanisms that regulate levels of manganese in the body. Somshuvra Mukhopadhyay, M.B.B.S., Ph.D., associate professor in the Division of Pharmacology and Toxicology and Hamm Centennial Fellow in Pharmacy, and a team of researchers have released new findings defining the first homeostatic regulatory pathway for manganese in mammalian systems. Identifying these pathways opens up new possible options to prevent or treat manganese-induced parkinsonism and other disorders linked to elevated manganese exposure.

Mukhopadhyay’s latest research article, "Up-regulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity," was 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 treatment. By focusing on understanding how our body regulates manganese levels, we were 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 basic science discoveries can be leveraged for possible therapeutic development."

Manganese is required for life, but at elevated levels, accumulates in the brain and causes parkinsonism. Parkinsonism due to manganese poisoning is seen in people exposed to high levels of the metal from occupational (e.g. welding) or environmental (e.g. drinking water) sources, individuals with liver disease because manganese is excreted by the liver or patients with certain genetic mutations. Mukhopadhyay's manuscript describes a regulatory pathway by which the body controls manganese levels. Elevations in manganese levels increase expression of SLC30A10, a protein that excretes manganese, thereby providing a pathway to reduce the amount of manganese in the body.

"These findings are a major step forward in our understanding of how the body regulates this biologically essential but potentially toxic metal and identify potential therapeutic approaches for protecting against the neurotoxic effects of elevated manganese exposure," says co-author Dr. Donald Smith, professor of microbiology and environmental toxicology at the University of California, Santa Cruz. "Historically, those 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 novel and promising approach for treating manganese poisoning." Smith is a co-inventor of the patent and contributed to the research article along with Chunyi Liu from the UT College of Pharmacy, Thomas Jursa from UC Santa Cruz and Michael Aschner from the Albert Einstein College of Medicine.

The paper also provides the involved mechanisms by showing that manganese increases SLC30A10 expression by activating a group of proteins called hypoxia-inducible factors, which regulate gene expression. Importantly, drugs that target hypoxia-inducible factors, called prolyl hydroxylase inhibitors, have already been developed for treatment for other diseases, such as renal anemia. The research team shows that these prolyl hydroxylase inhibitors protect cells and mice against the toxic effects of manganese, suggesting that these drugs may be potential therapeutic agents for the management of manganese-induced parkinsonism in humans.

"This is a significant development in advancing technology that will help manage and treat diseases like Parkinson’s. We are actively looking for potential partners who are interested in the development and commercialization of Dr. Mukhopadhyay's technology," said Kristen Falkenstein, senior licensing specialist in the Office of Technology Commercialization at UT Austin.

Mukhopadhyay's previous research related to manganese, SLC30A10 and parkinsonism has received considerable attention. The paper "SLC30A10 transporter in the digestive system regulates brain manganese under basal conditions while brain SLC30A10 protects against neurotoxicity" was named one of 2019’s Papers of the Year by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health (NIH). It also earned a 2020 Co-op Research Excellence Award for Best Paper, presented by The University of Texas at Austin’s Office of the Vice President for Research and the University Co-operative Society.

The Mukhopadhyay Lab in The University of Texas at Austin College of Pharmacy focuses on understanding cell biology of human disease. Its two major research projects involve parkinsonism and metal homeostasis, and intracellular trafficking of Shiga and related bacterial toxins. This research paper focuses primarily on the first research project. Metals, such as iron, manganese, and copper, are essential for life, but become toxic at elevated levels and cause severe neurological diseases, such as parkinsonism.

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