Study reveals promising new target for Parkinson's disease therapies

January 19, 2013

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.

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 that respond to the , leading to problems in , including tremors and difficulty walking.

The common understanding of MPTP's mechanism was that it entered the brain and was eventually converted to the 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 , 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- 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.

Explore further: Therapeutic avenues for Parkinson's investigated at UH

More information: dx.doi.org/10.1074/jbc.M112.402123

Related Stories

Therapeutic avenues for Parkinson's investigated at UH

August 23, 2012
Scientists at the University of Houston (UH) have discovered what may possibly be a key ingredient in the fight against Parkinson's disease.

New drug protects neurons in Parkinson's patients

September 5, 2012
(Medical Xpress)—Scientists at Emory University School of Medicine have identified a compound that boosts levels of a survival factor in neurons threatened by Parkinson's disease.

Ability to metabolize tamoxifen affects breast cancer outcomes, study confirms

December 27, 2012
For nearly a decade, breast cancer researchers studying the hormone therapy tamoxifen have been divided as to whether genetic differences in a liver enzyme affect the drug's effectiveness and the likelihood breast cancer ...

Recommended for you

Parkinson's is partly an autoimmune disease, study finds

June 21, 2017
Researchers have found the first direct evidence that autoimmunity—in which the immune system attacks the body's own tissues—plays a role in Parkinson's disease, the neurodegenerative movement disorder. The findings raise ...

Predicting cognitive deficits in people with Parkinson's disease

June 20, 2017
Parkinson's disease (PD) is commonly thought of as a movement disorder, but after years of living with PD approximately twenty five percent of patients also experience deficits in cognition that impair function. A newly developed ...

Pre-clinical study suggests Parkinson's could start in gut endocrine cells

June 15, 2017
Recent research on Parkinson's disease has focused on the gut-brain connection, examining patients' gut bacteria, and even how severing the vagus nerve connecting the stomach and brain might protect some people from the debilitating ...

Hi-res view of protein complex shows how it breaks up protein tangles

June 15, 2017
Misfolded proteins are the culprits behind amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and other neurodegenerative brain disorders. These distorted proteins are unable to perform their normal ...

CRISPR tech leads to new screening tool for Parkinson's disease

June 5, 2017
A team of researchers at the University of Central Florida is using breakthrough gene-editing technology to develop a new screening tool for Parkinson's disease, a debilitating degenerative disorder of the nervous system. ...

Infection with seasonal flu may increase risk of developing Parkinson's disease

May 30, 2017
Most cases of Parkinson's have no known cause, and researchers continue to debate and study possible factors that may contribute to the disease. Research reported in the journal npj Parkinson's Disease suggests that a certain ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.