Seminar Title: “Manganese Neurotoxicity: What can we Learn from Worms?”
PBB 229
Dr. Michael Aschner, PhD
Professor, Harold & Muriel Block Chair in Molecular Pharmacology,
Director, Einstein Center of Technology
Monday, April 24, 2023 from 12:15 pm – 1:15 pm
Research in our laboratory focuses on the interaction between genetics and the environment in triggering disease both during central nervous system (CNS) development and senescence. We are addressing metal uptake across the blood-brain barrier (BBB) and distribution in the brain (neurons and glia), specifically with methylmercury (MeHg) and manganese (Mn), as well as their cellular and molecular mechanisms of neurotoxicity. Our studies address mechanisms of transport and neurodegeneration in various experimental models (C. elegans, tissue cultures and rodents), as well as follow-up on the sequalae of heavy metal deposition in the brains of human neonates by means of magnetic resonance imaging (MRI).
Hypotheses presently tested include the following: (1) Modulation of C. elegans genes (aat, skn-1, daf-16) that are homologous to mammalian regulators of MeHg uptake and cellular resistance will modify dopaminergic neurodegeneration in response to MeHg exposure. (2) Under conditions of MeHg-induced oxidative stress, Nrf2 (a master regulator of antioxidant responses) coordinates the upregulation of cytoprotective genes that combat MeHg-induced oxidative injury, and that genetic and biochemical changes that negatively impact upon Nrf2 function increase MeHg’s neurotoxicity. (3) PARK2, a strong PD genetic risk factor, alters neuronal vulnerability to modifiers of cellular Mn status, particularly at the level of mitochondrial dysfunction and oxidative stress.
Our studies are ultimately designed to (1) shed novel mechanistic insight into metal-induced neurodegeneration; (2) provide novel targets for genetic or pharmacologic modulation of neurodegenerative disorders; (3) increase knowledge of the pathway involved in oxidative stress, a common etiologic factor in neurodegenerative disorders; (4) develop improved research models for human disease using knowledge of environmental sciences.
For more information, contact: Deirdre McAvoy at deirdre.mcavoy@uconn.edu