New research from the University of Pennsylvania School of Veterinary Medicine identifies mitochondrial CYP2D6 as a promising target for reducing brain damage linked to Parkinson’s disease.
Researchers often model Parkinson’s disease in animals by exposing them to MPTP, a contaminant found in the illicit opioid MPPP. MPTP selectively harms neurons that depend on dopamine, causing the motor symptoms typical of Parkinson’s: tremor, slowed movement, stiffness and balance problems.
The established explanation for MPTP toxicity holds that the compound crosses into the brain and is converted to the toxic metabolite MPP+ by the enzyme MAO-B, which resides on mitochondria in non-dopaminergic cells. That metabolite was thought to be transported into dopamine-producing neurons where it disrupts mitochondrial function and triggers cell death.
In a study published in the Journal of Biological Chemistry, the Penn team examined a different enzyme: mitochondrial CYP2D6. CYP2D6 is best known as a cytochrome P450 enzyme primarily localized to the endoplasmic reticulum, where earlier work suggested it may help protect against MPTP toxicity. More recently, however, researchers discovered that a fraction of CYP2D6 is targeted to mitochondria, a location that could change how it interacts with neurotoxic compounds.
The new findings show that mitochondrial CYP2D6 is capable of converting MPTP into the toxic MPP+. This mitochondrial metabolism links CYP2D6 directly to a pathway that can damage dopamine-producing neurons and contribute to Parkinson’s-like degeneration.
Genetic variation in CYP2D6 could be important. “About 80 percent of the human population has only one copy of CYP2D6, but the other 20 percent has variant forms of it and some populations have multiple copies,” said Narayan G. Avadhani, Harriet Ellison Woodward Professor of Biochemistry and chair of the Department of Animal Biology at Penn Vet. “In those people, the activity of mitochondrial CYP2D6 can be high, and there have been correlations between these variants and the incidence of Parkinson’s disease.”
Using cultured primary neurons, the team demonstrated that mitochondrial CYP2D6 actively oxidizes MPTP to MPP+. When they applied compounds that selectively inhibit CYP2D6 activity, that conversion was substantially reduced and neuronal degeneration was dramatically diminished. “If we add MPTP to dopamine-sensitive neurons and also add a CYP2D6 inhibitor, we see marked protection of the neuronal function,” Avadhani explained. “We believe this is a paradigm shift in how we think about the mechanism of Parkinson’s.”
Clinically, many MAO-B inhibitors are used to treat Parkinson’s symptoms, but these drugs can cause unwanted side effects. Targeting mitochondrial CYP2D6 could offer a more selective approach with potentially fewer off-target effects, because it focuses on the specific enzyme and organelle responsible for converting MPTP to its toxic form.
To validate and extend these results, Avadhani and colleagues are developing an animal model and using stem cell approaches to confirm the role of mitochondrial CYP2D6 in producing Parkinson’s-like features. Those next steps aim to establish whether inhibiting mitochondrial CYP2D6 can protect dopaminergic neurons in living systems and whether this strategy could be translated into safer, more targeted therapies for Parkinson’s disease.
Notes about this Parkinson’s disease research
Narayan G. Avadhani served as senior author. Members of the Penn Vet research team included Prachi Bajpai, Michelle C. Sangar, Shilpee Singh, Weigang Tang, Seema Bansal and Ji-Kang Fang. Collaborators from Vanderbilt University were Goutam Chowdhury, Qian Cheng, Martha V. Martin and F. Peter Guengerich. The study received support from the National Institutes of Health and the Harriet Ellison Woodward Endowment.
Contact: Katherine Unger Baillie – University of Pennsylvania
Source: University of Pennsylvania press release
Image Source: The Cytochrome P450 2D6 structure image is credited to BorisTM via Wikimedia Commons. The image is in the public domain.
Original Research: Abstract for “Metabolism of 1-Methyl-4-phenyl-1-2-3-6-tetrahydropyridine by Mitochondria-targeted Cytochrome P450 2D6: Implications in Parkinson’s Disease” published in the Journal of Biological Chemistry (published online December 20, 2012, doi: 10.1074/jbc.M112.402123).