Navigation Links
Parkinson's disease: Excess of special protein identified as key to symptoms and possible new target for treatment with widely used anti-cancer drug imatinib
Date:10/1/2010

Johns Hopkins scientists have discovered that the over-activation of a single protein may shut down the brain-protecting effects of a molecule and facilitate the most common form of Parkinson's disease. The finding of this mechanism could lead to important new targets for drugs already known to inhibit it, thus controlling symptoms of the disorder, which affects about 1 million older Americans.

Previous research demonstrated that a protein called parkin protects brain cells by "tagging" certain toxic elements that are then destroyed naturally. It was also known that mutations in the gene that holds the code for parkin cause rare, familial forms of PD. However, parkin's role remained unclear in sporadic late-onset PD, the prevalence of which is increasing as the population ages.

Results of the new study, published Sept. 7 in the Proceedings of the National Academy of Sciences (PNAS) Online Early Edition, indicate that an over-activation of a protein called c-Abl can shut down the activity of parkin and contribute to a build-up of toxic proteins that kill brain cells and enables the progression of PD.

C-Abl contributes to the regulation of cell death and is implicated in a host of diseases. It has already has proven to be a target for certain types of cancer-killing drugs, such as imatinib (Gleevec), the first drug designed to directly switch off a biochemical signal that directly targets a protein vital to cancer growth, says Ted Dawson, M.D., Ph.D., Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and scientific director of the Johns Hopkins Institute for Cell Engineering.

"Our new appreciation of c-Abl's role in sporadic PD suggests that we can give brain-permeable inhibitors of c-Abl to maintain parkin's normal protective function," Dawson says. "The testing of these already approved, well-tolerated drugs for a new use as a neuro-protective treatment for PD is a potentially exciting therapeutic arc that should be pursued."

The researchers first used a test called the Western blot to label certain proteins in neuron-like human cells in culture. They could see that c-Abl shut down the activity of parkin by measuring the levels of chemical tags on proteins that, in a healthy system, are marked for destruction. These "garbage" proteins, when overabundant, have been shown previously by Dawson's lab to be selectively toxic to neurons. When c-Abl was active, parkin's ability to tag those proteins was significantly decreased.

The team then incubated these cells with STI-571, a well-known c-Abl inhibitor marketed as imatinib or Gleevec. When compared to cultures not incubated with the compound, the inhibition of parkin's function by c-Abl was wholly prevented.

The c-Abl inhibitor, STI-571 was approved by the Food and Drug Administration in 2001 for the treatment of a cancer of white blood cells and in 2002 for the treatment of a rare form of stomach cancer. It works by blocking the activity of the abnormal c-Abl protein, which is much more active than the normal version. For a c-Abl inhibitor to be an effective treatment for Parkinson's disease, it would need to cross the blood-brain barrier, Dawson says.

Next, using a mouse which had been given drugs that cause Parkinson's-like traits, the team proved that when c-Abl is activated, parkin's function shuts down and as a result, garbage proteins accumulate and lead to a significant loss of neurons. The team also demonstrated that genetically altered mice in which c-Abl had been knocked out were protected against the same significant loss of neurons. They measured the loss of neurons by counting them: Wild-type (normal) mice lost about 8,000 neurons, while the genetically altered mice with the disabled c-Abl lost only about half that many.

Finally, the scientists turned to human brain tissue to look for evidence that c-Abl is a major regulator of parkin function. By comparing brain tissue of patients who died with Parkinson's disease with those who died of other causes, they established that when c-Abl shuts down Parkin, the "garbage" proteins accumulate and result is the death of neurons.

"With people living longer, lots more people are developing this common, debilitating neurological disorder," Dawson says, citing that one in 100 people are afflicted at the age of 60, and four times that many by the age of 80. "Now that we know the mechanism, it's important that we explore new, effective therapies that can slow or stop its progression."


'/>"/>

Contact: Maryalice Yakutchik
myakutc1@jhmi.edu
443-287-2251
Johns Hopkins Medical Institutions
Source:Eurekalert

Related medicine news :

1. Chronic Lyme disease: How often is it diagnosed and treated?
2. HIV/AIDS treatment curbs spread of disease: UBC-BC CfE study
3. Crohn's & Colitis Foundation National Event Helping Women Manage Inflammatory Bowel Disease: Two Women Physician Experts and Researchers in IBD on Interactive Webcast/Teleconference
4. Patients at high risk of recurrences of heart disease: Breakthrough in prevention
5. Understanding causes of cancer and chronic disease: The Canadian Partnership for Tomorrow Project
6. Thyroid Disease: The Hidden Epidemic
7. Excess Weight May Protect Women From Type of Glaucoma
8. Excess Weight in Older Women Linked to Diminished Memory
9. Fewer Excess Pounds May Mean Fewer Hot Flashes
10. Study shows a possible link between preschoolers cavities and excess body fat
11. High-school seniors with excessive daytime sleepiness have an increased risk of depression
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/25/2017)... ... June 25, 2017 , ... CareSet Labs released the Root NPI Graph today ... a new, greatly improved version of the Doctor Referral teaming dataset commonly available from ... and subsequently called the the “Doctor Referral Dataset” as released by Medicare and “DocGraph” ...
(Date:6/24/2017)... ... June 24, 2017 , ... The Pennsylvania Athletic ... Erie Bayfront and Erie Convention Center on June 8-10. The weekend consisted ... quiz bowl, award and scholarship presentations, and professional networking. , On Friday ...
(Date:6/23/2017)... ... June 23, 2017 , ... The Rhode Island ... Care Management Alerts and Dashboards, an innovative new service enabling healthcare providers to ... Care Management Alerts and Dashboards provide near real-time data about patients admitted to ...
(Date:6/23/2017)... ... June 24, 2017 , ... Studies show evidence that carotenoids ... risk of visual loss in these patients. , But how often do ophthalmologists and ... cessation to patients at risk of or with early symptoms of AMD? A ...
(Date:6/23/2017)... ... 2017 , ... Everybody has their own personal preference when it comes to ... some people don't like it at all. FindaTopDoc took a look at what makes ... can give readers a taste of their deepest, darkest fantasies and has the ability ...
Breaking Medicine News(10 mins):
(Date:6/9/2017)... INDIANAPOLIS , June 9, 2017 More ... a further effort to help spread lessons learned from ... the International Diabetes Federation (IDF) and Eli Lilly and ... for the second phase of the Bringing Research in ... reaffirming their commitment to helping people with diabetes effectively ...
(Date:6/8/2017)... 2017   Responding to Heath Ledger,s father,s ... of singer Chris Cornell in May, the mental ... a free online psychiatric drug side effects ... about psychotropic drug risks. The father of ... an accidental overdose, has called for tighter rules on prescription ...
(Date:6/7/2017)... , June 7, 2017 Endo International plc ... 7, 2017, the Hon. Joseph R. Goodwin , ... West Virginia , entered a case ... Pelvic Repair System Products Liability Litigation (the "MDL") that ... cases to provide expert disclosures on specific causation within ...
Breaking Medicine Technology: