Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers uncover new biological target for combating Parkinson's disease

26.08.2013
Compounds already exist to potentially treat both inherited and non-inherited cases

Researchers at Johns Hopkins and elsewhere have brought new clarity to the picture of what goes awry in the brain during Parkinson's disease and identified a compound that eases the disease's symptoms in mice.


This shows two cells with an excess of the protein AIMP2 (green), which interacts with the enzyme PARP1 (red) in the cells' nuclei.

Credit: Yun-Il Lee/Used with permission from Nature Neuroscience

Their discoveries, described in a paper published online in Nature Neuroscience on August 25, also overturn established ideas about the role of a protein considered key to the disease's progress.

"Not only were we able to identify the mechanism that could cause progressive cell death in both inherited and non-inherited forms of Parkinson's, we found there were already compounds in existence that can cross into the brain and block this from happening," says Valina Dawson, Ph.D., the director of the Stem Cell Biology and Neuroregeneration Programs at the Johns Hopkins University School of Medicine's Institute for Cell Engineering (ICE). "While there are still many things that need to happen before we have a drug for clinical trials, we've taken some very promising first steps."

Dawson and her husband, Ted Dawson, M.D., Ph.D., the director of ICE, have collaborated for decades on studies of the molecular chain of events that leads to Parkinson's. One of their findings was that the function of an enzyme called parkin, which malfunctions in the disease, is to tag a bevy of other proteins for destruction by the cell's recycling machinery. This means that nonfunctional parkin leads to the buildup of its target proteins, and the Dawsons and others are exploring what roles these proteins might play in the disease.

In the new study, the Dawsons collaborated with Debbie Swing and Lino Tessarollo of the National Cancer Institute, to develop mice whose genes for a protein called AIMP2 could be switched into high gear. AIMP2 is one of the proteins normally tagged for destruction by parkin, so the genetically modified mice enabled the research team to put aside the effects of defective parkin and excesses of other proteins and look just at the consequences of too much AIMP2.

The consequences were that the mice developed symptoms similar to those of Parkinson's as they aged, the group found. As in Parkinson's patients, the brain cells that make the chemical dopamine were dying. Since AIMP2 is known for its role in the process of making new proteins, the researchers thought the cell death was caused by problems with this process. But when graduate student Yunjong Lee looked at the efficiency of protein-making in the affected mice, everything appeared normal.

Looking for an alternative explanation, Lee tested how cells with excess AIMP2 responded to compounds blocking various paths to cell death, and found that the AIMP2 was activating a self-destruct pathway called parthanatos, discovered and named by the Dawsons years ago for the for poly(ADP-ribose), or "PAR," and the Greek word thanatos, which means "messenger of death."

The Dawsons had previously seen parthanatos set off after events like traumatic injuries or stroke — not by chronic disease. And there were more surprises to come. Lee found that AIMP2 triggered parthanatos by directly interacting with a protein called PARP1, which was long thought to respond only to DNA damage — not to signals from other proteins. Valina Dawson notes that AIMP2 is actually the second protein found to activate PARP1, but the idea that PARP1 is only involved in detecting and responding to DNA damage is still firmly entrenched in her field.

Since the Dawsons had been studying PARP1 for some time, they knew of compounds drug companies had designed to block this enzyme. Such drugs are already in the process of being tested to protect healthy cells during cancer treatment. Crucially, two of these compounds can cross over the blood-brain barrier that keeps many drugs from affecting brain cells. The research team used a compound that blocks PARP1, and Lee tested it on the mice with too much AIMP2. "Not only did the compound protect dopamine-making neurons from death, it also prevented behavioral abnormalities similar to those seen in Parkinson's disease," Lee says.

Though the results are encouraging, Valina Dawson cautions that there are hurdles that will need to be overcome before either of the brain-accessible compounds has a chance to make it into clinical trials. More extensive animal testing will need to be done, and with mice whose Parkinson's symptoms don't arise from genetically amped-up AIMP2 production. In addition, Dawson explains, in order for trials on any Parkinson's drugs to run effectively, measurable markers of the disease's severity need to be found. Ted Dawson and others at Johns Hopkins say they are now working on a separate project to do just that.

The current study was funded by the National Institute of Neurological Disorders and Stroke (grant number NS38377), the JPB Foundation, and the Intramural Research Program of the National Cancer Institute's Center for Cancer Research. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation, through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the foundation's Parkinson's disease programs.

Other authors of the study are Senthilkumar S. Karuppagounder, Joo-Ho Shin, Yun-Il Lee, Han Seok Ko, Haisong Jiang, Sung-Ung Kang, Byoung Dae Lee, Ho Chul Kang and Donghoon Kim, all of the Johns Hopkins University School of Medicine.

Related stories:

Johns Hopkins Team Explores Paris; Finds a Key to Parkinson's: http://www.hopkinsmedicine.org/news/media/releases/johns_hopkins_team

_explores_paris_finds_a_key_to_parkinsons_

Parkinson's Disease: Excess of Special Protein Identified As Key to Symptoms and Possible New Target for Treatment with Widely Used Anti-Cancer Drug: http://www.hopkinsmedicine.org/news/media/releases/parkinsons_disease_excess
_of_special_protein_identified_as_key_to_symptoms_and_possible_new_target
_for_treatment_with_widely_used_anti_cancer_drug
The Mouse Model: Less Than Perfect, Still Invaluable: http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_

events/articles_and_stories/model_organisms/201010_mouse_model.html

Shawna Williams | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel

nachricht Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Scientist invents way to trigger artificial photosynthesis to clean air

26.04.2017 | Materials Sciences

Ammonium nitrogen input increases the synthesis of anticarcinogenic compounds in broccoli

26.04.2017 | Agricultural and Forestry Science

SwRI-led team discovers lull in Mars' giant impact history

26.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>