Featured Research

from universities, journals, and other organizations

Promising new target for Parkinson's disease therapies

Date:
January 18, 2013
Source:
University of Pennsylvania
Summary:
With a new insight into a model of Parkinson's disease, researchers have identified a novel target for mitigating some of the disease's toll on the brain.

With a new insight into a model of Parkinson's disease, researchers from the University of Pennsylvania School of Veterinary Medicine have identified a novel target for mitigating some of the disease's toll on the brain.

Related Articles


Narayan G. Avadhani, Harriet Ellison Woodward Professor of Biochemistry and chair of the Department of Animal Biology at Penn Vet, was the senior author on the research. Other department members contributing to the work included Prachi Bajpai, Michelle C. Sangar, Shilpee Singh, Weigang Tang, Seema Bansal and Ji-Kang Fang. Co-authors from Vanderbilt University are Goutam Chowdhury, Qian Cheng, Martha V. Martin and F. Peter Guengerich.

To study Parkinson's, researchers have commonly mimicked the effects of the disease in animals by giving them a compound known as MPTP, a contaminant of the illicit drug MPPP, or synthetic heroin. MPTP causes damage to brain cells that respond to the neurotransmitter dopamine, leading to problems in muscle control, including tremors and difficulty walking.

The common understanding of MPTP's mechanism was that it entered the brain and was eventually converted to the toxic compound MPP+ by the enzyme MAO-B, which is located on the mitochondria of non-dopaminergic (or dopamine-sensitive) neurons. Scientists believed MPP+ was carried by the action of specific transporters into dopaminergic neurons, where it inhibited mitochondrial function and led to cell death.

In the new study, published in the Journal of Biological Chemistry, the Penn-led team turned its attention to yet another molecule, known as mitochondrial CYP2D6, which until recently has been largely uninvestigated. Previous studies in the investigators' laboratory showed that CYP2D6, a protein that is predominantly localized to cells' endoplasmic reticulum, was also targeted to their mitochondria.

Unlike MAO-B, the endoplasmic reticulum-associated CYP2D6 was thought to have a protective effect against MPTP toxicity. The authors now show that mitochondrial CYP2D6 can effectively metabolize MPTP to toxic MPP+, indicating a possible connection between mitochondrial CYP2D6 and Parkinson's.

"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," Avadhani said. "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."

Working with primary neuronal cells in culture, the researchers showed that mitochondrial CYP2D6 could actively oxidize MPTP to MPP+. When they introduced compounds that selectively inhibited the activity of CYP2D6, this conversion process was largely halted. Neuronal degeneration was also greatly reduced.

"If we add MPTP to dopamine-sensitive neurons and also add a CYP2D6 inhibitor, we see marked protection of the neuronal function," Avadhani said. "We believe this is a paradigm shift in how we think about the mechanism of Parkinson's."

A number of MAO-B inhibitors used in the clinical setting for treating Parkinson's disease have unwanted side effects. A mitochondrial CYP2D6 inhibitor represents a much more specific and direct target and may thus cause fewer troublesome side effects.

To take the next step with this finding, Avadhani and his colleagues are developing an animal model and using stem cells to confirm the significance of mitochondrial CYP2D6's role in the development of Parkinson's symptoms.

The study was supported by National Institutes of Health and the Harriet Ellison Woodward Endowment.


Story Source:

The above story is based on materials provided by University of Pennsylvania. Note: Materials may be edited for content and length.


Journal Reference:

  1. P. Bajpai, M. C. Sangar, S. Singh, W. Tang, S. Bansal, G. Chowdhury, Q. Cheng, J.-K. Fang, M. V. Martin, F. P. Guengerich, N. G. Avadhani. Metabolism of 1-Methyl-4-phenyl-1-2-3-6-tetrahydropyridine by Mitochondria-targeted Cytochrome P450 2D6: Implications in Parkinson's Disease. Journal of Biological Chemistry, 2012; DOI: 10.1074/jbc.M112.402123

Cite This Page:

University of Pennsylvania. "Promising new target for Parkinson's disease therapies." ScienceDaily. ScienceDaily, 18 January 2013. <www.sciencedaily.com/releases/2013/01/130118172337.htm>.
University of Pennsylvania. (2013, January 18). Promising new target for Parkinson's disease therapies. ScienceDaily. Retrieved March 29, 2015 from www.sciencedaily.com/releases/2013/01/130118172337.htm
University of Pennsylvania. "Promising new target for Parkinson's disease therapies." ScienceDaily. www.sciencedaily.com/releases/2013/01/130118172337.htm (accessed March 29, 2015).

Share This


More From ScienceDaily



More Mind & Brain News

Sunday, March 29, 2015

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

AAA: Distracted Driving a Serious Teen Problem

AAA: Distracted Driving a Serious Teen Problem

AP (Mar. 25, 2015) While distracted driving is not a new problem for teens, new research from the AAA Foundation for Traffic Safety says it&apos;s much more serious than previously thought. (March 25) Video provided by AP
Powered by NewsLook.com
Smartphone Use Changing Our Brain and Thumb Interaction, Say Researchers

Smartphone Use Changing Our Brain and Thumb Interaction, Say Researchers

Reuters - Innovations Video Online (Mar. 25, 2015) European researchers say our smartphone use offers scientists an ideal testing ground for human brain plasticity. Dr Ako Ghosh&apos;s team discovered that the brains and thumbs of smartphone users interact differently from those who use old-fashioned handsets. Jim Drury went to meet him. Video provided by Reuters
Powered by NewsLook.com
Many Don't Know They Have Alzheimer's, But Their Doctors Do

Many Don't Know They Have Alzheimer's, But Their Doctors Do

Newsy (Mar. 24, 2015) According to a new study by the Alzheimer&apos;s Association, more than half of those who have the degenerative brain disease aren&apos;t told by their doctors. Video provided by Newsy
Powered by NewsLook.com
A Quick 45-Minute Nap Can Improve Your Memory

A Quick 45-Minute Nap Can Improve Your Memory

Newsy (Mar. 23, 2015) Researchers found those who napped for 45 minutes to an hour before being tested on information recalled it five times better than those who didn&apos;t. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins