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Excellence Cluster set to go

The nerve-center of the operation

Munich, 03/05/2013

Many neurological diseases show striking parallels in pathology. Here LMU biochemist Christian Haass outlines the collaborative strategy the new research network SyNergy is using to dissect the unifying mechanisms.

Picture: Katrin Strecker/LMU

It is now clear that a single mechanism plays a key role in the pathogenesis of two apparently quite distinct neurological diseases. Can you briefly describe the course of these two illnesses, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)?
Haass: FTD is a typical neurodegeneration syndrome that primarily affects the frontal cortex of the forebrain. This leads to drastic alterations in personality, which also places an immense burden on patients’ relatives. ALS is quite different. Here, the axons of motor neurons – the neuronal processes that control muscular activity – die. The earliest symptoms are striking muscle twitches, and eventually the muscles actually waste away. Patients lose the ability to swallow and speak. Disease progression is rapid and death usually ensues within 3 to 4 years. And neither of these conditions can be regarded as really rare.

Two very dissimilar conditions, one would imagine.
Yes, certainly. But doctors have repeatedly noted that some ALS patients develop symptoms typical of FTD, and vice versa. Moreover, mutations in the same gene are associated with the emergence of ALS in some individuals and FTD in others. That strongly suggests to me that the two conditions result from a single cause, although they seem so different.

What then is the common underlying mechanism, which you and your colleague Bettina Schmid have just identified?
First, I should fill in some of the background. In neurodegenerative diseases, insoluble protein aggregates are typically found in the nerve cells affected, as in the case of Alzheimer‘s. These precipitates are symptomatic and may be toxic. In the case of ALS and FTD, the clumps mainly consist of a single protein called TDP-43. TDP-43 is normally restricted to the cell nucleus, but in ALS it forms extranuclear aggregates, which suggests a drastic loss of its normal function. Using the zebrafish as an experimental model, we specifically inactivated the gene that codes for this protein. We expected that this would lead, above all, to the death of motor neurons. But the first thing we noticed in the mutant fish was that blood flow was severely compromised, and there were striking abnormalities in the patterning of the vasculature.

But that wasn’t all you discovered...
We also found that, in these mutants, an aberrant form of a muscle-specific protein is overproduced, which is also observed – in the frontal cortex of FTD patients with TDP-43 aggregates. And the muscle tissue in the brain is responsible for constriction of the vasculature – which brings us back to the issue of the blood supply. This network of connections also neatly illustrates the rationale behind the structure of the SyNergy Cluster, which is to look beyond the limits implied by conventional classifications, and ask whether more general symptoms might not also play a role in the pathogenesis of some neurological diseases.

What sorts of symptoms do you have in mind?
By definition, neurodegeneration leads to nerve cell loss, but it is also characterized by defects in blood flow and by local inflammatory reactions. All of these processes interact with each other. To get back to ALS for a moment, the neurologists in the SyNergy Cluster are now asking whether ALS patients have problems with the blood supply to the brain. So far, no one has really looked closely. And our zebrafish studies provide the first clear hints that the blood supply could be a major factor.

Such an integrative approach to neurological illnesses has seldom been utilized up to now.
It’s something that doesn’t come easy to clinicians, or to researchers for that matter. We are forced to think in narrowly defined categories, otherwise things get too complicated. In 1990, when I began to study neurodegeneration, inflammation processes were known to play a significant role in Alzheimer’s. Then we discovered amyloid, the protein fragment that is a basic component of the typical plaques found in Alzheimer’s, and we concentrated our attention on that. We are trained to do things in this way. We have to be focused, if we want to be successful. But, at some point, when one has obtained a detailed mechanistic understanding of a given aspect of a problem, one should broaden one’s field of view. That’s what we are now doing in SyNergy. Everyone involved, clinicians and basic researchers, is now beginning to look at the bigger picture.

How much bigger?
We are interested in all forms of neurological disease, but our major focus is on neurodegenerative processes, which account for around two-thirds of all neurological diseases. But multiple sclerosis is also in our sights. MS is not generally thought of as a degenerative disease, at least not in Germany, but recent findings made by some of our members suggest that this view is incorrect. MS is also a degenerative condition, in which the neuronal axons die. Perhaps there are overlaps in pathogenesis here too.

Can you give us an example of a typical synergistic SyNergy project?
A new one got underway only last week. In all vertebrates, redundant connections between nerve fibers and muscles are pruned away during the post-natal period. One might call this a benign type of neurodegeneration, if the term were not self-contradictory. We have obtained clear indications that there are mechanistic similarities between this process and what happens in the neurons that die off in FTD. Some of the enzymes involved are apparently misregulated in FTD. We want to follow this up, and we are now gearing up to perform the decisive experiments. And incidentally, the idea for the project developed out of discussions that I had with Thomas Misgeld of the Technical University in Munich, who is Co-Spokesman for SyNergy, after he had given a short talk at one of our meetings. The real point of SyNergy is to bring the right people together. Without that, he and I might never have had this kind of exchange.

SyNergy’s declared goal is to convert new insights from basic research into real benefits for patients as fast as possible. Have you come up with a structure that facilitates this?
The whole translational process, i.e., the application of results from molecular biology in the clinical setting, and the incorporation of clinical findings into research on mechanisms, is underdeveloped. It is one of the biggest problems in biomedicine here in Germany – and not only here. We haven’t trained the right kind of expert. We don’t have enough clinicians who are adept at research, so the pool of young clinical researchers we need simply does not exist. For this reason, we have integrated a dedicated educational program into the structure of SyNergy, which enables young neurologists to complete their specialist training in a shorter time. They are then assigned to one of our laboratories, so that they can devote the time saved to a project of their own choice in an established research setting.

Interview: math

SyNergy – Munich Cluster for Systems Neurology is a new Excellence Cluster which will fill a gap in the research landscape by taking an integrative and collaborative approach to the study of the common mechanisms that underlie a number of neurological diseases. The new venture, for which LMU obtained funding in the last round of the Excellence Initiative, has just begun its work. The Cluster combines the talents of several dozen basic researchers and clinicians – neurologists and radiologists, molecular biologists, biophysicists and bioinformatics specialists – who will follow this new strategy to analyze how degenerative, inflammatory and vascular pathologies interact to give rise to neurological illnesses.

The SyNergy Cluster will not only perform basic research but is also designed to promote clinical research. Funding for the Cluster comes from Federal and State Governments in the context of the Excellence Initiative, and is assured until 2017. In addition to LMU as coordinating institution, the Technical University of Munich (TUM), the German Center for Neurodegenerative Diseases (DZNE), the Helmholtz Center Munich and the Max Planck Institutes for Biochemistry, Neurobiology and Psychiatry are partners in the venture.

Prof. Dr. Christian Haass holds the Chair of Metabolic Biochemistry at LMU, and is Spokesman for both the Munich Branch of the German Center for Neurodegenerative Diseases (DZNE) and the new SyNergy Cluster at LMU.

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