Press releases

 

Nov 4 2014
11:19

Structure of the ABC transporter, elucidated thanks to pioneering structure analysis/Publication in Nature

How cells defend themselves against antibiotics and cytostatic agents

FRANKFURT. ABC-Transporters are proteins that are embedded in the cell membrane and facilitate the transport across cellular barriers not only of an almost unlimited variety of toxic substances, but also of substances that are essential for life. They also play a role in the development of antibiotic resistance. A research group at the Goethe University in Frankfurt am Main, in co-operation with American colleagues, has now succeeded in elucidating the detailed structure of this transporter.

"On the one hand, ABC transporters cause diseases such as cystic fibrosis, while on the other hand they are responsible for the immune system recognising infected cells or cancer cells," explains Professor Robert Tampé from the Institute for Biochemistry at the Goethe University. The considerable medical, industrial and economic significance of ABC transporters is also based on the fact that they cause bacteria and other pathogens to become resistant to antibiotics. Likewise, they can help cancer cells to defend themselves against cytostatic agents and thus determine whether chemotherapy will succeed.

For the first time, the group led by Robert Tampé, in collaboration with colleagues at the University of California in San Francisco, succeeded in determining the structure of an asymmetrical ABC transporter complex with the aid of a high-resolution cryo-electron microscope. "Over a period of five years, we have successfully implemented a number of innovative, methodological developments. These have enabled us to gain insights that previously were unimaginable," says Tampé.

The researchers report in the current issue of the renowned scientific journal, Nature that they have succeeded in investigating a single frozen ABC transport complex at a subnanometer resolution that has never before been achieved. For this purpose, they used a newly developed single electron camera, new imaging processes and specific antibody fragments in order to determine the structure and conformation of the dynamic transport machine.

"The combination of physical, biotechnological, biochemical and structural biological methods has led to a quantum leap in the elucidation of the structure of macromolecular complexes," says Tampé. The method facilitates the targeted development of a trend-setting therapeutic approach. 

Publication:
JungMin Kim et al.: Subnanometre-resolution electron cryomicroscopy structure of a heterodimeric ABC exporter, nature 2.11.2014, doi:10.1038/nature13872

Information: Prof. Dr. Robert Tampé, Goethe University Frankfurt, Institute of Biochemistry, Phone +49(0)69 798-29475, tampe@em.uni-frankfurt.de; www.biochem.uni-frankfurt.de/

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Oct 9 2014
11:15

Biomarkers and target proteins identified in vulnerable neurons

Parkinson: How toxic proteins stress nerve cells

FRANKFURT Parkinson's Disease is the second most common neurodegenerative disorder. In Germany alone, almost half a million people are affected. The focus of the disease is the progressive degeneration of dopamine-producing nerve cells in a certain region of the midbrain, the substantia nigra. Misfolded proteins are the cause. Until recently, it was unclear why damage is confined to specific nerve cells. A team or researchers led by Frankfurt neurophysiologists has now defined how this selective disease process begins using a genetic mouse model of Parkinson´s disease.

The progressive death of a certain type of nerve cells – dopaminergic neurons - in the substantia nigra causes dopamine deficiency, which is the major cause for the motor deficits in Parkinson patients. Although it is possible to therapeutically compensate the dopamine deficiency for a certain period of time, by e.g. administration of L-dopa or dopamine agonists, these therapies do not stop the progressive death of neurons. 

In the last two decades, researchers have identified gene mutations and toxic protein aggregates to cause neurodegeneration, with the protein a-synuclein having an essential role. Until recently, it was unclear why only specific types of nerve cells, such as dopaninergic neurons in the substantia nigra, are affected by this process, while others, also expressing the mutant a-syncuclein such as dopaminergic neurons in the immediate vicinity, survive the disease process with little damage.

The research group led by Dr. Mahalakshmi Subramaniam and Prof. Jochen Roeper at the Institute for Neurophysiology at the Goethe University, in collaboration with researchers from Frankfurt's Experimental Neurology Group and from Freiburg University, demonstrated for the first time how sensitive dopaminergic substantia nigra neurons functionally respond to toxic proteins in a genetic mouse model. A mutated a-synculein gene (A53T), which causes Parkinson's Disease in humans, is expressed in the mouse model. 

In the current issue of the Journal of Neuroscience, the researchers report that the sensitive dopaminergic substantia nigra neurons respond to the accumulation of toxic protein by significantly increasing the electric activity in the affected midbrain regions. In contrast, the less sensitive, neighboring dopaminergic neurons were not affected in their activity. "This process begins as early as one year before the first deficits appear in the dopamine system, and as such it presents an early functional biomarker that may have future potential for preclinical detection of impending Parkinson's Disease in humans," explains Prof. Jochen Roeper. "The potential for early preclinical detection of subjects at risk is essential for the development of neuroprotective therapies."

The Frankfurt group, also identified a regulatory protein, an ion channel, which is causes the increase in electric activity and the associated stress in nerve cells in response to oxidative damage.  This channel provides a direct new target protein for the neuroprotection of dopaminergic neurons. In brain slices, the dysfunction of this ion channel acting as an "electric brake" for dopamine neurons was reversible just by adding redox buffers.  If therapeutic drugs could reduce the channel´s redox sensitivity in future mouse models, the death of dopaminergic neurons in the substantia nigra might be prevented.  Currently, the researchers are studying whether similar processes occur with other Parkinson genes and in aging itself. "The long-term objective is to investigate the extent to which these results from mice might be transferred to humans," says Roeper.

Publikation: Mahalakshmi Subramaniam et al.: Mutant a-Synuclein Enhances Firing Frequencies in Dopamine Substantia Nigra Neurons by Oxidative Impairment of A-Type Potassium Channels, The Journal of Neuroscience, October 8, 2014 • 34(41):13586 –13599. doi:10.1523/JNEUROSCI.5069-13.2014.

Information: Prof. Dr. med. Jochen Roeper, Institute of Neurophysiology Goethe University Frankfurt, Phone +49(0)69 6301–84091, roeper@em.uni-frankfurt.de.

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Oct 8 2014
11:09

A research group lead by scientists at the Goethe University Frankfurt discover details on how clouds form

"Superglue" for the atmosphere

FRANKFURT. New insights into cloud formation were obtained by scientists from the Goethe University of Frankfurt in an international collaboration. They found out that amines could play an important role in aerosol formation. They act as a kind of “superglue”. Aerosol particles influence the climate through their role in cloud formation because clouds can only form if so-called cloud condensation nuclei (CCN) are available.

It has been known for several years that sulfuric acid contributes to the formation of tiny aerosol particles, which play an important role in the formation of clouds. The new study by Kürten et al. shows that dimethylamine can tremendously enhance new particle formation. The formation of neutral (i.e. uncharged) nucleating clusters of sulfuric acid and dimethylamine was observed for the first time.

Previously, it was only possible to detect neutral clusters containing up to two sulfuric acid molecules. However, in the present study molecular clusters containing up to 14 sulfuric acid and 16 dimethylamine molecules were detected and their growth by attachment of individual molecules was observed in real-time starting from just one molecule. Moreover, these measurements were made at concentrations of sulfuric acid and dimethylamine corresponding to atmospheric levels (less than 1 molecule of sulfuric acid per 1 x 1013 molecules of air).

The capability of sulfuric acid molecules together with water and ammonia to form clusters and particles has been recognized for several years. However, clusters which form in this manner can vaporize under the conditions which exist in the atmosphere. In contrast, the system of sulfuric acid and dimethylamine forms particles much more efficiently because even the smallest clusters are essentially stable against evaporation. In this respect dimethylamine can act as “superglue” because when interacting with sulfuric acid every collision between a cluster and a sulfuric acid molecule bonds them together irreversibly. Sulphuric acid as well as amines in the present day atmosphere have mainly anthropogenic sources. Sulphuric acid is derived mainly from the oxidation of sulphur dioxide while amines stem, for example, from animal husbandry. The method used to measure the neutral clusters utilizes a combination of a mass spectrometer and a chemical ionization source, which was developed by the University of Frankfurt and the University of Helsinki. The measurements were made by an international collaboration at the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN (European Organization for Nuclear Research).

The results allow for very detailed insight into a chemical system which could be relevant for atmospheric particle formation. Aerosol particles influence the Earth’s climate through cloud formation: Clouds can only form if so-called cloud condensation nuclei (CCN) are present, which act as seeds for condensing water molecules. Globally about half the CCN originate from a secondary process which involves the formation of small clusters and particles in the very first step followed by growth to sizes of at least 50 nanometers. The observed process of particle formation from sulfuric acid and dimethylamine could also be relevant for the formation of CCN. A high concentration of CCN generally leads to the formation of clouds with a high concentration of small droplets; whereas fewer CCN lead to clouds with few large droplets. Earth’s radiation budget, climate as well as precipitation patterns can be influenced in this manner. The deployed method will also open a new window for future measurements of particle formation in other chemical systems. 

Publication:

Kürten, A., Jokinen, T., Simon, M., Sipilä, M., Sarnela, N., Junninen, H., Adamov, A., Almeida, J., Amorim, A., Bianchi, F., Breitenlechner, M., Dommen, J., Donahue, N. M., Duplissy, J., Ehrhart, S., Flagan, R. C., Franchin, A., Hakala, J., Hansel, A., Heinritzi, M., Hutterli, M., Kangasluoma, J., Kirkby, J., Laaksonen, A., Lehtipalo, K., Leiminger, M., Makhmutov, V., Mathot, S., Onnela, A., Petäjä, T., Praplan, A. P., Riccobono, F., Rissanen, M. P., Rondo, L., Schobesberger, S., Seinfeld, J. H., Steiner, G., Tomé, A., Tröstl, J., Winkler, P. M., Williamson, C., Wimmer, D., Ye, P., Baltensperger, U., Carslaw, K. S., Kulmala, M., Worsnop, D. R., and Curtius, J.: Neutral molecular cluster formation of sulfuric acid-dimethylamine observed in real-time under atmospheric conditions, Proc. Natl. Acad. Sci. USA, doi/10.1073/pnas.1404853111, 2014.

Contact: Dr. Andreas Kürten, Institute for Atmospheric and Environmental Sciences, Goethe University Frankfurt am Main, Telefon 0049 (69) 798-40256, E-Mail: kuerten@iau.uni-frankfurt.de

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Sep 25 2014
11:02

Soil bacteria contribute to the taste and smell

On the trail of the truffle flavour

FRANKFURT. Truffles, along with caviar, are among the most expensive foods in the world. Because they grow underground, people use trained dogs or pigs to find them. But the distinctive smell of truffles is not only of interest to gourmets. A group of German and French scientists under the direction of the Goethe University Frankfurt have discovered that the smell of white truffles is largely produced by soil bacteria which are trapped inside truffle fruiting bodies.

White truffles from the Piedmont region in Italy can reach 5,000 Euro per kilogram, and black truffles from the Périgord region in Southern France as much as 2,000 Euro per kilogram. Particularly large specimens even fetch prices of up to 50,000 Euro per kilogram at auctions. Connoisseurs search for the precious delicacies near hazelnut trees, oaks and some species of pine. This is because truffles grow in a symbiotic relationship with the trees. For scientists truffles are therefore a model organism to investigate how symbiosis evolved between plants and fungi.

Truffles are also useful to study fungal smell and flavour. Understanding how flavours are created is indeed very important to the food industry. Yeasts and bacteria which make cheese and wine have been researched in depth, but little is known about how the flavour of other organisms, including truffles, is created.

Over the past 10 years, researchers already suspected that micro-organisms trapped inside truffle fruiting bodies contributed to the flavour. "When the genome of the black Perigord truffle was mapped in 2010, we thought that the fungus had sufficient genes to create its flavour on its own", junior professor Richard Splivallo from the Institute for Molecular Life Sciences at the Goethe University explained.

The team made up of German and French scientists studied the white truffle Tuber borchii. It is native to Europe but has been recently introduced in New Zealand and Argentina. The researchers were able to show that bacteria produce a specific class of volatile cyclic sulphur compounds, which make up part of the distinctive truffle smell. Dogs and pigs are able to find truffles underground thanks to the slightly sulphuric smell.

"However, our results cannot be transferred to other types of truffles", Splivallo says, "because the compounds we investigated are only found in the white truffle Tuber borchii." For this reason, in the future they plan to study compounds which are found in the Périgord and Piermont truffles and are common to all types of truffles. "We don't just want to know which part of the truffle flavour is produced by bacteria. We are also interested in how the symbiosis between fungi and microorganisms has evolved and how this benefits both symbiotic partners."

Publication:
Splivallo R, Deveau A, Valdez N, Kirchhoff N, Frey-Klett P, Karlovsky P. (2014). Bacteria associated with truffle-fruiting bodies contribute to truffle aroma. Environmental Microbiology. DOI: 10.1111/1462-2920.12521

Information: Junior-Prof. Richard Splivallo, Institute for Molecular Bio Sciences, Campus Riedberg, Tel.: 0049(0)69/ 798- 42193, Splivallo@bio.uni-frankfurt.de.

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Sep 10 2014
10:59

Long lost Roman fort discovered

Hitting the jackpot on a dig in Gernsheim

FRANKFURT. In the course of an educational dig in Gernsheim  in the Hessian Ried, archaeologists from Frankfurt University have discovered a long lost Roman fort: A troop unit made up out of approximately 500 soldiers (known as a cohort)  was stationed there between 70/80 and 110/120 AD. Over the past weeks, the archaeologists found two V-shaped ditches, typical of this type of fort, and the post holes of a wooden defensive tower as well as other evidence from the time after the fort was abandoned.

An unusually large number of finds were made. This is because the Roman troops dismantled the fort and filled in the ditches when they left. In the process they disposed of a lot of waste, especially in the inner ditch. "A bonanza for us," according to Prof. Dr. Hans-Markus von Kaenel from the Goethe University Institute of Archaeology. "We filled box after box with shards of fine, coarse and transport ceramics; dating them will allow us to determine when the fort was abandoned with greater accuracy than was possible before".

Up until now, little was known about Roman Gernsheim, even though findings from the Roman era have been cropping up here since the 19th century. "Previously, the only thing that seemed certain based on the finds was that  an important village-like settlement, or "vicus", must have been located here from the 1st to the 3rd century, comparable with similar villages which have already been shown to have existed in Groß-Gerau, Dieburg or Ladenburg", explained dig leader Dr. Thomas Maurer. He has been travelling from Frankfurt to South Hessia for years and has published his findings in a large publication about the North Hessian Ried during Roman imperial times.

"It was assumed", continued Maurer, "that this settlement had to have been based on a fort, since it was customary for the families of the soldiers to live outside the fort in a village-like settlement." "We really hit the jackpot with this excavation campaign", said a delighted Prof. Dr. Hans-Markus von Kaenel. "The results are a milestone in reconstructing the history of the Hessian Ried during Roman times." For almost 20 years now, von Kaenel has been studying this area with the help of his colleagues and students using surveys, digs, material processing and analyses. The results have been published in over 50 articles.

The Romans built the fort in Gernsheim in order to take control of large areas to the east of the Rhine in the seventh decade of the 1st century AD and to expand the traffic infrastructure from and to the centre of Mainz-Mogontiac. The fact that Gernsheim am Rhein was very important during Roman times is supported by its favourable location for travel: A road branches off from the Mainz – Ladenburg – Augsburg highway in the direction of the Main Limes. One can assume that a Rhine harbour existed as well, but this couldn't be verified during the course of this dig. "That was always unlikely on account of the chosen location", according to Maurer. Gernsheim continued to expand during the 20th century, and this expansion threatened to wipe out more and more of the archaeological traces. While the Roman remains were mostly still hidden under fields and gardens in the year 1900, they were gradually built over and thus lost to methodical archaeological research. The last plot of any measurable size where it might still be possible to make findings from the Roman era was an area in the south west of the city between the B44 and the River Winkelbach. But in 1971 the excavators moved in here as well. Maurer added: "At the time, a few volunteers from the Heritage Conservation Society were barely able to save a few Roman finds.

On August 4 of this year, the annual educational dig run by the Goethe University Institute of Archaeology began on one of the few remaining properties which had not been built on; a double lot at Nibelungenstraße 10-12. "According to my maps of those Gernsheim sites which could be located, we are at the far western edge of the area in which the  finds are concentrated, right at the edge of the lower terrace, since the nearby River Winkelbach flows into the Rhine basin from here", explained dig leader Maurer. Isolated Roman finds were made on almost all neighbouring properties during the 1970s and 1980s. "Thus the site seemed to be a worthwhile location for a dig, which turned out to be very much the case."

Over the past five weeks, 15 students of the "Archaeology and History of the Roman Provinces" course carefully stripped away the soil, mapped and documented the finds, and recovered and packaged them by type. The work was supported by Frankfurt archaeologists from the Hessian State Office for the Preservation of Historical Monuments (Hessen ARCHÄOLOGIE, Darmstadt branch) and by the Art and History Society of Schöfferstadt Gernsheim. Some members of this society, which also operates the local museum, supported the dig team on a daily basis. The documentation and the findings from this excavation campaign form the basis for a thesis at the University, work on which will start in the winter semester.

Pictures can be downloaded from: www.muk.uni-frankfurt.de/51885456

Information:  Dr. Thomas Maurer, Institute of Archaeology, West End Campus, Phone: 0177-5672114, t.maurer@em.uni-frankfurt.de

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