Project exploring role of manganese in Parkinson’s awarded $3.4M grant
Study will build on earlier work conducted by Florida A&M researchers
A five-year, $3.4 million grant from the National Institute of Environmental Health Sciences is supporting research into how manganese exposure may increase the risk of developing Parkinson’s disease.
Manganese is an essential mineral the body needs in small amounts. However, high-level exposure, such as through certain pesticides, mining, or metal alloy production, can lead to manganism, a neurological condition with symptoms similar to Parkinson’s disease.
The project, titled “Mechanism of Manganese-induced neurotoxicity via microglial Leucine Rich Repeat Kinase 2 (LRRK2),” will be led by Eun-sook Yu Lee, PhD, professor at the Florida A&M University College of Pharmacy and Pharmaceutical Sciences (FAMU CoPPS).
“This study is important to educate the people who are living in the area with high levels of manganese found in contaminated water and air pollution that this exposure may cause manganism,” Lee said in a university news story.
Researchers to study LRRK2 activity in mouse models
Parkinson’s disease is caused by the progressive loss of dopaminergic neurons, the nerve cells that produce dopamine, in a specific area of the brain called the substantia nigra. The loss of dopamine, a brain-signaling molecule involved in motor control, ultimately leads to the disease’s motor symptoms.
What exactly triggers the loss of dopaminergic neurons is not fully known, but neuroinflammation, or inflammation in the brain, and toxic accumulation of abnormally folded proteins are thought to play a role. Certain genetic mutations, including in the LRRK2 gene, may also be associated with the development of Parkinson’s.
In earlier studies, the team discovered manganese exposure elevated both the levels and activity of LRRK2 in two models: mice with the G2019S mutation in the LRRK2 gene and lab-grown microglia, the brain’s resident immune cells.
“Mutation of LRRK2 gene is most commonly associated with genetic Parkinson’s disease cases, and is known to increase LRRK2 activity. Manganese also increases LRRK2 activity,” Lee said. “This means that manganese-induced abnormally high LRRK2 activity may contribute to the development of Parkinson’s disease, particularly in those people who have LRRK2 mutations,” said Lee.
Now, the team will investigate the mechanisms behind manganese-induced increases in LRRK2 expression and activity in microglia, as well as how this affects neuronal health, using a cellular model combining microglia and neurons. They will also examine whether microglial LRRK2 activity contributes to neuronal toxicity and motor deficits in mouse models.
“We will use cell cultures and a genetic mouse model which deletes the LRRK2 gene in the specific cell type in the brain called microglia, to determine the role of LRRK2 in microglial cells associated with causing manganese toxicity,” Lee said.
Lee’s latest achievement received praise from one of her colleagues.
“This award is a testament to Dr. Lee’s ongoing outstanding research accomplishments and a clear recognition of her pioneering work on manganese neurotoxicity,” said Karam Soliman, PhD, associate dean for FAMU-CoPPS.
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