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Frankfurt scientists discover new molecular mechanisms that eliminate intracellular damages – Mutations in this pathway trigger neurodegenerative diseases
FRANKFURT. Quality control is important – this is not only applicable to industrial production but also true for all life processes. However, whereas an enterprise can start a large-scale recall in case of any doubt, defects in the quality control systems of cells are often fatal. This is seen in particular in neurodegenerative diseases such as Alzheimer's, Parkinson's, or amyotrophic lateral sclerosis (ALS), in which fundamental mechanisms of cellular quality control fail.
A Frankfurt research team led by Ivan Dikic, Professor for Biochemistry, now successfully decoded molecular details enabling a better understanding of two neurodegenerative diseases. Their work focuses on "autophagy" as a central element of cellular quality control. Autophagy literally means "self-eating", and refers to a sophisticated system in which cellular waste is specifically detected, surrounded by membranes, and removed. Typical targets are harmful or superfluous proteins or cell organelles, even pathogens such as bacteria or viruses can be eliminated via this pathway.
Together with colleagues from Jena, Aachen, and The Netherlands, the team of Ivan Dikic has now identified a new autophagy receptor, the so-called FAM134B protein. In the online issue of the renowned journal Nature, the researchers report a new function of FAM134B in the constant renewal of the endoplasmic reticulum (ER), an important cell organelle. FAM134B ensures proper breakdown and disposal of dysfunctional ER.
"Too little FAM134B leads to an uncontrolled dilation and expansion of this organelle, which is harmful for the cell", explains Ivan Dikic. "The discovery of FAM134B as a new autophagy receptor is already a milestone. Even more exciting is the connection to a rare neuronal hereditary disease". Collaborators from the Human Genetics Department at the University Hospital of Jena, PD Ingo Kurth and Professor Christian Hübner, already demonstrated in 2009 that mutations in FAM134B cause the death of sensory neurons in a disorder called hereditary sensory and autonomic neuropathy type II (HSAN II). The exact function of FAM134B, however, remained unknown until now.
HSAN II is a very rare hereditary disease in which both pain and temperature sensitivity and perspiration are impaired. For example, affected patients burn and hurt themselves easily, because they cannot feel heat and pain signals. Mutation of FAM134B in a mouse model leads to a similar syndrome "The mutated protein cannot function as a receptor. With these discoveries we have taken a big step to understanding the molecular causes of this neuropathy. At the same time, the importance of autophagy in cellular quality control is underlined", explains Dikic.
His laboratories at the Institute for Biochemistry II (IBC II) and at the Buchmann Institute for Molecular Life Sciences (BMLS) recently participated in another groundbreaking study of a neurodegenerative disease, ALS. Typically, ALS leads to death after three to four years due to the massive loss of motor neurons ALS (Amyotrophic lateral sclerosis ) is a devastating disease characterized by loss of motor neurons and neurodegeneration, usually leading to death within 3-4 years. Despite being classified as rare disease, public awareness is very high, fueled by celebrity patients like Stephen Hawking and culminating in last years’ Ice Bucket Challenge, the first charity campaign with global impact. Still, there is no treatment for ALS, despite intensive research in the field.
As reported in the title story of Nature Neuroscience’s May issue, an international team has now progressed significantly in understanding gene defects responsible for ALS. The scientists discovered that mutations in a specific enzyme, Tank-binding kinase (TBK1), occur more frequently in families with ALS. The Dikic lab was particularly involved in clarifying the function of TBK1 and was able to show that the mutations found in patients interrupt the interaction of TBK1 with the autophagy receptor optineurin. Optineurin is involved, for example, in the elimination of aggregated proteins and bacterial infection defense. Co-lead author Dr. Benjamin Richter comments: " For me as a medical doctor working in basic science this story represents the ideal case of explaining the pathophysiology of a disease by a collaborative effort across disciplines. ".
"The two studies show in an unparalleled way how general concepts can be developed from individual findings", emphasizes Ivan Dikic. When cellular quality control in neurons fails over a long time, the consequences for the overall organism are disastrous. "Autophagy has crystalized as a common central mechanism of cellular quality control in neurodegenerative disease", says Dikic.
Ivan Dikic (49) is leading his lab at the Goethe University in Frankfurt am Main since 2002; he is the director of Institute for Biochemistry II since 2009; and was the Founding Director of the Buchmann Institute for Molecular Life Sciences at the Riedberg Campus. Born in Croatia, he studied medicine in Zagreb, followed by a doctorate in natural sciences at the University of New York and the establishment of his first independent research group at the Ludwig Institute for Cancer Research in Uppsala (Sweden). In 2013, he received the Leibniz Prize of the German Research Foundation (DFG), the most prestigious German scientific prize. Furthermore, he has been honored with numerous other awards, including the Ernst Jung Prize for Medicine (2013), the William C. Rose Award of the American Society for Biochemistry and Molecular Biology (2013), and the German Cancer Prize (2010). He is a member of the German National Academy of Sciences and EMBO (European Molecular Biology Organisation) In 2010 he won an advanced investigator grant from the European Research Council (ERC), and he is the spokesperson for the LOEWE focus project Ubiquitin Networks, in the context of which parts of the now published work were done.
Image for download:
A. Khaminets et al.: Regulation of endoplasmic reticulum turnover by selective autophagy. Nature, doi: 10.1038/nature14498, Advance Online Publication (AOP): http://www.nature.com/nature
A. Freischmidt et al.: Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia Natur Neuroscience, Nature Neuroscience
Contact: Prof. Dr. Ivan Dikic, Goethe-Universität Frankfurt, Phone +49 (0)69 6301 5964, Email: firstname.lastname@example.org
Reconstruction of Arctic climate conditions in the Cretaceous period
FRANKFURT. Scientists at the Goethe University Frankfurt and at the Senckenberg Biodiversity and Climate Research Centre working together with their Canadian counterparts, have reconstructed the climatic development of the Arctic Ocean during the Cretaceous period, 145 to 66 million years ago. The research team comes to the conclusion that there was a severe cold snap during the geological age known for its extreme greenhouse climate. The study published in the professional journal Geology is also intended to help improve prognoses of future climate and environmental development and the assessment of human influence on climate change.
The Cretaceous, which occurred approximately 145 million to 66 million years ago, was one of the warmest periods in the history of the earth. The poles were devoid of ice and average temperatures of up to 35 degrees Celsius prevailed in the oceans. "A typical greenhouse climate; some even refer to it as a 'super greenhouse' ", explains Professor Dr. Jens Herrle of the Goethe University and Senckenberg Biodiversity and Climate Research Centre, and adds: "We have now found indications in the Arctic that this warm era 112 to 118 million years ago was interrupted for a period of about 6 million years."
In cooperation with his Canadian colleague Professor Claudia Schröder-Adams of the Carleton University in Ottawa, the Frankfurt palaeontologist sampled the Arctic Fjord Glacier and the Lost Hammer diapir locality on Axel Heiberg Island in 5 to 10 metre intervals. "In so doing, we also found so-called glendonites", Herrle recounts. Glendonite refers to star-shaped calcite minerals, which have taken on the crystal shape of the mineral ikaite. "These so-called pseudomorphs from calcite to ikaite are formed because ikaite is stable only below 8 degrees Celsius and metamorphoses into calcite at warmer temperatures", explains Herrle and adds: "Thus, our sedimentological analyses and age dating provide a concrete indication for the environmental conditions in the cretaceous Arctic and substantiate the assumption that there was an extended interruption of the interglacial period in the Arctic Ocean at that time."
In two research expeditions to the Arctic undertaken in 2011 and 2014, Herrle brought 1700 rock samples back to Frankfurt, where he and his working group analysed them using geochemical and paleontological methods. But can the Cretaceous rocks from the polar region also help to get a better understanding of the current climate change? "Yes", Herrle thinks, elaborating: "The polar regions are particularly sensitive to global climatic fluctuations. Looking into the geological past allows us to gain fundamental knowledge regarding the dynamics of climate change and oceanic circulation under extreme greenhouse conditions. To be capable of better assessing the current man-made climate change, we must, for example, understand what processes in an extreme greenhouse climate contribute significantly to climate change." In the case of the Cretaceous cold snap, Herrle assumes that due to the opening of the Atlantic in conjunction with changes in oceanic circulation and marine productivity, more carbon was incorporated into the sediments. This resulted in a decrease in the carbon dioxide content in the atmosphere, which in turn produced global cooling.
The Frankfurt scientist's newly acquired data from the Cretaceous period will now be correlated with results for this era derived from the Atlantic, "in order to achieve a more accurate stratigraphic classification of the Cretaceous period and to better understand the interrelationships between the polar regions and the subtropics", is the outlook Herrle provides.
Jens O. Herrle, Claudia J., Schröder-Adams, William Davis, Adam T. Pugh, Jennifer M. Galloway, and Jared Fath: Mid-Cretaceous High Arctic stratigraphy, climate, and Oceanic Anoxic Events, in: Geology, 19 Mai 2015, 10.1130/G36439.1 Open Access
Pictures are available for download here: www.senckenberg.de/presse
Information: Prof. Dr. Jens O. Herrle, Senckenberg Biodiversity and Climate Research Centre, Faculty of Geoscience and Geography, Goethe University Frankfurt, Phone +49 (0)69 798 40180, email@example.com
Two out of ten plastic rings release chemicals with hormone-like effect
FRANKFURT. In laboratory tests, two out of ten teethers, plastic toys used to sooth babies’ teething ache, release endocrine disrupting chemicals. One product contains parabens, which are normally used as preservatives in cosmetics, while the second contains six so-far unidentified endocrine disruptors. The findings were reported by researchers at the Goethe University in the current issue of the Journal of Applied Toxicology.
"The good news is that most of the teethers we analyzed did not contain any endocrine disrupting chemicals. However, the presence of parabens in one of the products is striking because these additives are normally not used in plastic toys", says Dr. Martin Wagner, of the Department Aquatic Ecotoxicology at the Goethe University. The substances detected – methyl, ethyl and propyl parabens – can act like natural oestrogen in the body and, in addition, inhibit the effects of androgens such as testosterone. The EU Commission recently banned two parabens in certain baby cosmetics, because of concerns over their health effects.
"Our study shows that plastic toys are a source of undesirable chemicals. Manufacturers, regulatory agencies and scientists should investigate the chemical exposure from plastic toys more thoroughly", Wagner concludes from the study. The additives have only limited benefits for the quality of the product, but can represent a potential health issue. This is especially true for babies and infants, whose development is orchestrated by a delicately balanced hormonal control and who are more susceptible to chemicals exposures than adults.
Elisabeth Berger, Theodoros Potouridis, Astrid Haeger, Wilhelm Püttmann and Martin Wagner: Effect-directed identification of endocrine disruptors in plastic baby teethers, in: Journal of Applied Toxicology, 18.5.2015, DOI: 10.1002/jat.3159
Information: Dr. Martin Wagner, Department Aquatic Ecotoxicology, Goethe University, Phone: +49 (0) 69 798-42149, firstname.lastname@example.org; Elisabeth Berger, Phone: +49 (0) 60516 1954-3117, email@example.com
Neurobiologist Amparo Acker-Palmer receives an ERC Advanced Grant of 2.5 million Euros for five years
FRANKFURT. Neurons and blood vessels often traverse the body side by side, a fact observed as early as the 16th century by the Flemish anatomist Andreas Vesalius. Only over the last ten years, however, researchers have discovered that the growth of neuronal and vascular networks is controlled by the same molecules. Prof. Amparo Acker-Palmer, a pioneer in this area, performs groundbreaking research on the communication between neurons and blood vessel cells in the brain. She hopes to use her findings to gain important insights into brain diseases such as dementia and mental illness. The European Research Council will fund her project with an Advanced Investigator Grant of 2.5 million Euros over the next five years.
“Most interesting is the interaction between neurons and blood vessels in the cerebral cortex. To date, we know very little about how neurons communicate with endothelial cells in order to structure a functional network in the brain.” explains Acker-Palmer. She plans to assess these processes in the layering of the cerebral cortex during embryonic development. Here, neuronal cells migrate in an inside out manner, while blood vessels grow in the opposite direction, from the pial surface towards the ventricular surface. Since these two growth processes are coordinated, Acker-Palmer suspects that they are controlled by the same signaling molecules. How dysfunction in the crosstalk may lead to cognitive impairments is one of the focuses of her research.
As model organisms her team uses genetically altered mice and zebrafish. Translucent zebrafish are the best suitable vertebrate model to visualize in vivo the dynamic events of cell-to-cell communication at the neurovascular interface. High-resolution electron microscopes will also be used to study these close connections between endothelial cells in the blood capillaries and glial cells at the blood-brain barrier. Glial cells wrap around the blood capillaries and prevent harmful substances from the blood stream from entering the brain.. Acker-Palmer and her team aim at deciphering the molecular signaling pathways regulating the neurovascular interface. “If we can intervene in the mechanism and temporarily open the blood-brain barrier, we can insert active agents and find new approaches for treating dementia and mental illness,” says the neurobiologist.
Amparo Acker-Palmer, born in Sueca, Valencia, Spain in 1968, studied biology and biochemistry at the University of Valencia, where she obtained her PhD in 1996. Then she moved to the European Molecular Biology Laboratory (EMBL) in Heidelberg to perform her postdoctoral work. In 2001, she moved to Martinsried, near Munich, to head an independent junior research group on signal transduction at the Max Planck Institute for Neurobiology. In 2007, she became Professor at the “Macromolecular Complexes” Center of Excellence at the Goethe University Frankfurt. Acker-Palmer is the Chair of the Molecular and Cellular Neurobiology Department at Goethe University Frankfurt since 2011. She received a Gutenberg Research College (GRC) fellowship from Johannes Gutenberg University Mainz in 2012, and she one of the leading scientists in the Rhine-Main Neuroscience Network (rmn2). In 2014, Acker-Palmer joined the Max Planck Society as Max Planck Fellow at the MPI for Brain Research in Frankfurt. Amparo Acker-Palmer is member of the Leopoldina German Academy of Natural Scientists and the Academia Europaea. She received the Paul Ehrlich Award for Young Scientists in 2010.
Pictures are available for download here: www.uni-frankfurt.de/55539781
Prof. Amparo Acker-Palmer.
Mouse brain: The microscope image of a mouse brain illustrates the close interaction between neurons (green), astrocytes (blue), and blood vessels (red) in the brain. The various cell populations appear in a specific pattern and interact with the neighboring cells.
Zebrafish: In vivo-Imaging of the blood circulation system in a three-day-old zebrafish larva. The left picture shows a side view of the head, the middle picture a side view of the trunk and the right picture a back view of the head. Fluorescent reporter genes reveal that the blood vessels (green) are fully formed at this point. The individual blood cells (red) can also be seen circulating in the blood vessels.
Information: Prof. Amparo Acker-Palmer, Institute of Cellular Biology and Neuroscience, Buchmann Institute of Molecular Life Sciences, Campus Riedberg, Tel.: (069) 798-42563, Acker-Palmer@bio.uni-frankfurt.de.
Biologist Stefanie Dimmeler receives an ERC Advanced Grant of 2.5 million Euros for five years
FRANKFURT. About 70 percent of our genes provide the blueprint for biomolecules whose function is only now being discovered – non-coding RNAs. Instead of being translated into proteins, they seem to perform steering functions in the body. Stefanie Dimmeler was one of the first researchers to prove that the sub-group of micro-RNAs plays a role in regenerating blood vessels. She has now received the coveted ERC Advanced Investigator Grant from the European Research Council (ERC), which will allow her to study another large group of non-coding RNAs. She believes that this group plays a role in creating heart attacks, strokes and cancer. ERC has awarded her 2.5 million Euros over the next five years.
“If you asked me what was special about the evolutionary development of human beings, I would say it´s the more than 30,000 non-coding RNA, most of which we only share with primates,” says Stefanie Dimmeler. From the perspective of her research area, cardiovascular regeneration, it is especially noteworthy that vascular illnesses like arteriosclerosis, which causes heart attacks, only occur in their typical form in humans. There are many indicators that long, non-coding RNAs, lncRNAs for short, control these illnesses. They affect the inside layer of the blood vessels, known as endothelial cells, and help supply the organs and tissues with oxygen and nutrients.
The technologies used to track these lncRNAs and their complex functions are much more complicated than finding proteins. Dimmeler and her working group identified two candidates, Angiolnc1 and Angiolnc2, that regulate the functions of endothelial cells. Now she wants to study the molecular epigenetic mechanisms that these two lncRNAs use to trigger vascular illnesses. The goal of this research is to identify new treatments for preventing arteriosclerosis, in order to reduce the incidence of heart attacks and strokes.
In the third part of her project, Dimmeler will study whether ring-shaped lncRNAs, which have special protection once they are released into the blood, can be used as biomarkers for identifying illnesses in the vascular system or the heart. To this end, she will work with her group to develop tests that can be used to find these biomolecules in patients’ blood during the various stages of cardiovascular illnesses.
Prof. Stefanie Dimmeler, born in 1967, studied Biology at the University of Constance, where she received her doctorate in 1993. After two years as a research assistant at the University of Cologne, she went to Goethe University, where she was promoted to professor in 1998 in the Department of Experimental Medicine. In 2001, she accepted a position as a professor in the Molecular Cardiology Department at Goethe University. She has been the Director of the Institute of Cardiovascular Regeneration, in the Center for Molecular Medicine, since 2008. She is the co-speaker of the DFG-funded “Cardiopulmonary Systems” Excellence Cluster, the “LOEWE Center for Cell and Genetic Therapy” funded by the State of Hesse, and the German Center for Cardiovascular Research (DZHK) funded by the German Ministry for Education and Research (BMBF) at the Rhine-Main site. She is a member of the Macromolecular Complexes Excellence Cluster as well as several specialized research areas. From 2008 to 2012, she was a member of the German Ethics Commission. Stefanie Dimmeler has received numerous research prizes, including the renowned Gottfried Wilhelm Leibniz Prize from the German Research Foundation and the Ernst Jung Prize for Medicine.
Pictures are available for download here: www.uni-frankfurt.de/55538604
Prof. Stefanie Dimmeler.
Blood vessels: An image of blood vessels in the heart (shown in red). The large vessel is surrounded by smaller vessels (capillaries). The nuclei are shown in blue, and the neurons are green.
Information: Prof. Stefanie Dimmeler, Institute for Cardiovascular Regeneration, Niederrad Campus, Main Office: Claudia Herfurth, Tel.: (069) 6301-6667, firstname.lastname@example.org.