In a recent article in the Proceedings of the National Academy of Sciences (PNAS), ongoing research into the causes of manganese-induced parkinsonism has revealed a possible treatment option. Somshuvra Mukhopadhyay, M.B.B.S., Ph.D., associate professor in the Division of Pharmacology and Toxicology and James E. Bauerle Centennial Fellow, and a team of researchers have released new findings that the PHD2 inhibitor, which is the cell’s master oxygen sensor, has a second physiologically essential function – to also act as the cell’s manganese sensor.
The latest PNAS article from the Mukhopadhyay Lab is “PHD2 enzyme is an intracellular manganese sensor that initiates the homeostatic response against elevated manganese.” Authors include College of Pharmacy graduate student Kerem Gurol, research scientist Dr. Eun Jeong Cho, faculty members Dr. Kevin Dalby and Dr. Walter Fast as well as Thomas Jursa and Dr. Donald R. Smith from the University of California at Santa Cruz.
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 previous research 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.
But the mechanism by which mammalian systems sense a change in manganese to initiate the homeostatic HIF response, which Mukhopadhyay’s group previously showed was necessary to increase SLC30A10, was unknown. The new paper now shows that elevated manganese outcompetes the catalytic iron of prolyl hydroxylase domain 2 (PHD2) enzyme, which otherwise target HIFs for degradation and thus inactivates PHD2 and upregulates HIF signaling for homeostatic control of manganese.
Mukhopadhyay and his researchers currently have a provisional patent in conversion for the use of PHD2 inhibitors for the treatment of manganese-induced parkinsonism.
“Manganese-induced parkinsonism has been reported since the 1800s and remains of high biomedical concern, yet finding a treatment for this disease has remained elusive,” says Mukhopadhyay. “Our line of investigation is providing a rational strategy for increasing manganese elimination to treat this disease.”
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.