Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Hereditary neurodegeneration linked to ADP-ribose modification

12.03.2013
Attaching chains of the small molecule ADP-ribose to proteins is important for a cell’s survival and the repair of DNA damage, making this process a promising target for the development of new cancer drugs.

Researchers have now identified a much sought after enzyme that removes such ADP-ribose modifications from proteins by studying a genetic mutation that causes neurodegenerative disease in humans.

These findings, published today in The EMBO Journal, suggest that not only addition but also removal of ADP-ribose from proteins is essential for normal cell function.

Poly(ADP-ribose) chains have key roles in the repair of cellular DNA damage, as well as in the control of gene expression and cell death. Pharmacological drugs called PARP inhibitors prevent the addition of ADP-ribose or ADP-ribose polymers to proteins. Several of these drugs are undergoing clinical trials for the treatment of different types of cancers.
EMBO Young Investigator Ivan Ahel, a group leader at the Paterson Institute for Cancer Research at the University of Manchester, has been studying the underlying molecular processes, including an enzyme that shortens such chains piece by piece. “An enzyme that could completely uncouple ADP-ribose from proteins has remained elusive, even though such a cellular activity has been known to exist for more than 30 years,” commented Ahel. “Our approach has been to combine clinical, biochemical and structural studies to see if we could pin point this enzyme activity in humans.”

The eventual breakthrough came when Ahel and his collaborators Scott Williams (National Institutes of Health, USA), Gyula Timinszky and Andreas Ladurner (both from Ludwig Maximilians University Munich) teamed up with a group of clinical geneticists lead by Reza Sharifi at the Human Genetics Research Center at St George's University of London. “By studying genetic mutations in a group of patients with severe neurodegenerative disease, we found a gene that was mutated in a family that had several cases of severe progressive neurodegenerative and seizure disorder,” remarked Sharifi. The product of this gene, which was named TARG1 (for terminal ADP-ribose protein glycohydrolase), exhibited the long-sought-after enzyme activity that fully removes ADP-ribose from proteins, and was further required for the proliferation of cells and response to DNA damage.
The researchers note that further work is needed to investigate the exact cellular processes where TARG exerts its functions, and to understand in more detail why mutation of this gene causes neurodegenerative disease. “Our discovery suggests a new pathogenic mechanism that may operate in a wider range of neurodegenerative disorders, the genetics of which generally remain very poorly understood,” concluded Sharifi.

Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease

Reza Sharifi, Rosa Morra, C. Denise Appel, Michael Tallis, Barry Chioza, Gytis Jankevicius, Michael A. Simpson, Ivan Matic, Ege Ozkan, Barbara Golia, Matthew J. Schellenberg, Ria Weston, Jason G. Williams, Marianna N. Rossi, Hamid Galehdari, Juno Krahn, Alexander Wan, Richard C. Trembath, Andrew H. Crosby, Dragana Ahel, Ron Hay, Andreas G. Ladurner, Gyula Timinszky, R. Scott Williams, Ivan Ahel

Read the paper:
http://www.nature.com/emboj/journal/vaop/ncurrent/full/emboj201351a.html
doi: 10.1038/emboj.2013.51

Further information on The EMBO Journal is available at http://www.nature.com/emboj

Media Contacts
Barry Whyte
Head | Public Relations and Communications
barry.whyte@embo.org

Hartmut Vodermaier
Senior Editor, The EMBO Journal
Tel: +49 6221 8891 401
hartmut.vodermaier@embo.org

About EMBO
EMBO is an organization of more than 1500 leading researchers that promotes excellence in the life sciences. The major goals of the organization are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information, and help build a European research environment where scientists can achieve their best work.

EMBO helps young scientists to advance their research, promote their international reputations and ensure their mobility. Courses, workshops, conferences and scientific journals disseminate the latest research and offer training in techniques to maintain high standards of excellence in research practice. EMBO helps to shape science and research policy by seeking input and feedback from our community and by following closely the trends in science in Europe.

Yvonne Kaul | idw
Further information:
http://www.embo.org

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>