While seeking targets to attack Huntington’s disease, an incurable inherited neurodegenerative disorder, neurobiologists of the research group of Professor Erich Wanker (Max Delbrück Center) found what they were looking for. Using a filtering strategy borrowed from criminologists, they systematically filtered interaction networks of various biological databases until they found the protein CRMP1. In subsequent lab experiments they showed that it acts like a “chaperone”, ensuring that the protein huntingtin (HTT) behaves correctly and does not misfold or clump. Dysregulated modulation of HTT by CRMP1 is regarded as a causal mechanism of Huntington’s disease (Genome Research)*.
Huntington's disease, historically referred to as St. Vitus' dance, was discovered in 1872 by the American physician George Huntington. It is a rare, incurable hereditary disease (6:100 000), which usually appears in middle adulthood.
Systematic network filtering in gene and protein databases: First the researchers led by Professor Erich Wanker of the Max Delbrück Center (MDC) constructed a protein network (PP1) around the huntingtin protein HTT and then limited their investigation area step by step (PP2, PP3, PP4). Thus, they could identify the protein CRMP1, which protects against Huntington’s disease, and is present in Huntington patients in too low quantities. (Graphic: Gautam Chaurasia, Miguel Andrade/ Copyright: MDC)
The affected individuals suffer from uncontrollable jerking movements, dementia and psychiatric disorders. Death occurs about 15 years after onset of the disease. For children of an affected parent, the risk of also having Huntington's disease is 50 percent. The gene for the HTT protein is located on chromosome 4. If it is mutated, the protein is also altered.
Characteristic of the toxic HTT protein is an elongated sequence of 40 and more glutamine building blocks (glutamine is one of the amino acid building blocks for proteins). These assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are regarded as a cause for the development of Huntington’s disease.
How to master the flood of data?
The objective of the research project of Professor Wanker and his colleagues was to find proteins that interact with the huntingtin protein (HTT) and prevent its misfolding, clumping, functional neuronal impairment and neurotoxicity. To start off, the researchers asked themselves: “How can we extract the information we are seeking from the various gene and protein databases? Among the thousands of proteins and additional thousands of protein-protein interactions, how can we filter out those that interact with the mutated protein HTT and in particular with the elongated glutamine sequence?”
When we use a search engine we enter a certain term for which the system returns loads of data. But in the case of this research project, this was not feasible because the MDC researchers wanted to avoid drowning in a flood of data from various biodatabases. That is why they decided to use a computational network filtering procedure in which information from different areas is linked to each other in a step by step process.
In order to limit their search, Dr. Martin Stroedicke, Dr. Yacine Bounab, Dr. Gautam Chaurasia, Dr. Matthias Futschik and Professor Wanker made use of research findings from previous studies on Huntington’s disease. In this disease, the brain regions that are mainly affected have to do with movement (motor skills) as well as moods and feelings. One region in particular, the caudate nucleus, is massively affected in Huntington’s disease; most of the movement disorders – and the most severe ones – arise from this region.
The idea was first to construct a protein network around the protein HTT in order to identify its direct and indirect “cooperation partners”. For this purpose, the MDC researchers scoured previously published gene and protein data of the candidate regions of the brain, both of Huntington patients and healthy controls. In doing so, they identified 1319 protein interactions and discovered among them more than 500 proteins that interact directly or indirectly with the protein HTT.
In a second step, they searched for HTT interaction partners in healthy brains and in other body tissues to filter out only the proteins that are relevant for the brain. Next, they narrowed down the search in the third step to the most affected region in Huntington's disease, thethe caudate nucleus. They compared the data of 38 patients with Huntington’s disease with data from 32 healthy controls. During this process they discovered 13 proteins that interact directly or indirectly with the HTT protein. Strikingly, in the patients with Huntington’s disease these 13 proteins are present in smaller amounts than in the control group.
Too little of the protective protein CMRP1 in patients with Huntington’s disease
In the third step, the MDC researchers succeeded in filtering one protein among these 13 proteins that directly targets the elongated glutamine sequence of the HTT protein. This protein, abbreviated CRMP1 (for collapsin response mediator protein 1), plays a key role in the development of nerve cells and their communication. On the basis of the data, the researchers were able to determine that this protective protein CRMP1 occurs in Huntington's disease patients in too small amounts.
Findings verified in the laboratory
The findings the researchers gained by filtering the databases were then tested in cell culture in the laboratory and with transgenic mice – they additionally carry the gene for Huntington’s disease in their genome – and healthy mice. This confirmed what the findings of the databases had already indicated, namely that the quantity of CRMP1 protein in the transgenic animals in comparison to the healthy mice was in fact very low. It is unclear, however, why this is so.
The next question was then whether the protein CRMP1 has an effect on the mutant HTT protein. Because there is too little of this protein in Huntington’s disease, by means of a genetic trick the researchers accelerated the production of the protein CRMP1 in transgenic Huntington fruit flies (Drosophila melanogaster). Climbing experiments showed that CRMP1 in fact improved the movement disorders of the animals.
No therapy yet
By means of these animal studies, the MDC researchers were able to demonstrate experimentally that CRMP1 in larger quantities eliminates the malfunction of HTT. It prevents the aggregation of HTT, thus improving the function of nerve cells in Huntington's disease. “With the filtering of molecular interaction networks, we have developed a simple but effective method to identify those proteins that interact directly with the disease-causing protein HTT,” said Professor Wanker.
In addition to this newly discovered protein there are now also other proteins that could serve as targets for future therapies and which the researchers could include in their network. They hope their findings will help develop a therapy for Huntington’s disease. “But that will still take many years,” Prof. Wanker pointed out.
*Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity
Martin Stroedicke,1 Yacine Bounab,1 Nadine Strempel,1 Konrad Klockmeier,1Sargon Yigit,1 Ralf P. Friedrich,1,8 Gautam Chaurasia,2,8 Shuang Li,1 Franziska Hesse,1Sean-Patrick Riechers,1 Jenny Russ,1 Cecilia Nicoletti,3 Annett Boeddrich,1 Thomas Wiglenda,1 Christian Haenig,1 Sigrid Schnoegl,1 David Fournier,1 Rona K. Graham,4 Michael R. Hayden,4 Stephan Sigrist,5 Gillian P. Bates,6 Josef Priller,3 Miguel A. Andrade-Navarro,1 Matthias E. Futschik,1,7 and Erich E. Wanker1
1Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany,
2Institute of Theoretical Biology, Humboldt University of Berlin, 10115 Berlin, Germany,
3Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany,
4Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada,
5Institute of Biology/Genetics, Free University Berlin, 14195 Berlin, Germany,
6Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, United Kingdom,
7Centre for Molecular and Structural Biomedicine, Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal
Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
Barbara Bachtler | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
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...
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...
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...
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...
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...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences