Goethe-Universit盲t 鈥� Press releases

看片软件 PR & Communication Department聽

Nov 15 2024

10:05

Researchers identify a mechanism that enhances the accuracy of protein precursor processing聽

Slow editing of protein blueprints leads to cell death

An international research team has uncovered a new mechanism crucial to the production of cellular proteins. When this mechanism is disrupted, the blueprints used by the cell to produce proteins are inaccurately edited through a process called splicing. The study, led by 看片软件 Frankfurt, sheds light on how specific mutations may lead to the retinal disease retinitis pigmentosa. Importantly, these findings could also open the door to new diagnostic tests and treatments for a range of other diseases, including certain cancers, Parkinson鈥檚, and Alzheimer鈥檚.

FRANKFURT. Genes contain the essential building instructions for life, guiding cells on which amino acids to assemble in what sequence to produce specific proteins. The human genome codes for about 20,000 such instructions. 鈥淣evertheless, our cells can produce several hundred thousand different proteins,鈥� explains Prof. Ivan 膼iki膰 from the Institute of Biochemistry II at 看片软件 Frankfurt.

This diversity is enabled by a process known as 鈥渟plicing.鈥� When a cell requires a protein, it generates a copy of the relevant instructions in the cell nucleus. During splicing, this transcript undergoes modification: a cellular editing complex, the spliceosome, removes certain segments. The outcome varies depending on which parts are cut out, resulting in distinct blueprints for different proteins.

Splicing accuracy enhanced

This process is crucial for the life of the cell. 鈥淭he spliceosome is composed of multiple components that secure production of functional proteins controlling cellular life,鈥� explains 膼iki膰. 鈥淚f this complex is disrupted, it can lead to the death of the affected cell. For this reason, spliceosome inhibitors are considered as potential anti-cancer drugs.鈥� However, the downside is that a complete blockade of this "editing office" also affects healthy cells, resulting in significant side effects of any spliceosome inhibitor developed so far.

In an international study led by 看片软件, researchers have now identified a mechanism that interferes with the splicing process in a more subtle way. It is related to a specific part of the spliceosome, composed of three subunits known as U4/U6.U5.

鈥淲e already knew that certain mutations in these subunits are linked to the eye disease retinitis pigmentosa,鈥� says Dr. Cristian Prieto-Garcia from the Institute of Biochemistry II, the first author of the study. 鈥淲hat we didn鈥檛 yet understand was the exact impact of these mutations.鈥�

Experiments on zebrafish combined with mathematical calculations

In experiments with zebrafish, the team has now managed to fill this knowledge gap. Their findings reveal that spliceosome subunits U4, U5 and U6 are normally stabilized as a complex by a protein called USP39. However, when subunits are mutated or USP39 is absent, the stability of the tripartite complex is compromised, causing the spliceosome to lose precision. During splicing, U4/U6.U5 normally ensures the immediate and correct re-joining of loose ends after a transcript has been cut. Without USP39, or when subunits are mutated, this re-joining is delayed.

鈥淭his increases the likelihood of incorrect connections, as we were able to show in computer simulations,鈥� explains Prieto-Garcia. This results in incorrectly edited transcripts, on the basis of which the cell then produces dysfunctional proteins. These accumulate and can form aggregates inside the cell. Cells have a waste disposal system to clear out defective molecules, and this protective mechanism was activated in cells lacking USP39. Over time, however, this "garbage disposal" became overwhelmed by the protein aggregates, leading to cell death in the zebrafish retina.

Surprising discovery

鈥淭he discovery of this mechanism was unexpected,鈥� emphasizes Prof. 膼iki膰. 鈥淲e suspect it may also explain why retinal cells in retinitis pigmentosa patients die. Defective splicing variants might also play a role in the development of neurodegenerative diseases like Alzheimer鈥檚 or Parkinson鈥檚. On the other hand, this mechanism may be targeted by new therapeutic approaches for types of cancer that are highly dependent on the correct function of the spliceosome.鈥�

Some highly aggressive tumors produce large amounts of USP39 and related splicing factors, likely due to their high division rate: To maintain constant protein production, they require highly precise splicing, a function that USP39 provides. 鈥淏locking USP39 in these cancer cells could selectively kill them,鈥� 膼iki膰 explains. 鈥淗ealthy cells, on the other hand, with their much lower division activity, would be spared. This is an approach that we are currently investigating.鈥�

Publication: Cristian Prieto-Garcia, Vigor Matkovic, Thorsten Mosler, Congxin Li, Jie Liang, James A. Oo, Felix Haidle, Igor Macinkovi膰, Alfredo Cabrera-Orefice, Rayene Berkane, Giulio Giuliani, Fenfen Xu, Anne-Claire Jacomin, Ines Tomaskovic, Marion Basoglu, Marina E. Hoffmann, Rajeshwari Rathore, Ronay Cetin, Doha Boutguetait, S眉leyman Bozkurt, Mar铆a Clara Hern谩ndez Ca帽谩s, Mario Keller, Jonas Busam , Varun Jayeshkumar Shah, Ilka Wittig, Manuel Kaulich, Petra Beli, Wojciech P. Galej, Ingo Ebersberger, Likun Wang, Christian M眉nch, Alexandra Stolz, Ralf P. Brandes, William Ka Fai Tse, Stefan Eimer, Didier Y. R. Stainier, Stefan Legewie, Kathi Zarnack, Michaela M眉ller-McNicoll, Ivan Dikic: Pathogenic proteotoxicity of cryptic splicing is alleviated by ubiquitination and ER-phagy. Science (2024);

Image for download:

Caption: USP39 stabilizes the spliceosome (green), which cuts out unneeded parts (grey and purple) of the mRNA. If USP39 is missing, some of the mRNA is poorly processed. This results in misfolded proteins, which lead to stress and cell death. Grahics: Molecular Signaling Group IBC2, 看片软件

Further information
Professor Ivan 膼iki膰
Head of "Molecular Signaling" Group
Institute of Biochemistry II
看片软件 Frankfurt
Tel: +49 (0) 69 6301-5652
dikic@biochem2.uni-frankfurt.de
Homepage:

Twitter/X: @goetheuni @IBC2_GU

Nov 14 2024

16:24

Ute Lewitzka appointed 鈥� Heightened focus on suicide prevention within the Faculty of Medicine

Germany鈥檚 first-ever professorship in suicide studies and suicide prevention established at 看片软件 Frankfurt

Dr. Ute Lewitzka has been appointed Germany鈥檚 first professor of suicide studies and suicide prevention. Her appointment at 看片软件 Frankfurt took effect on November 1, 2024. One of her main objectives is the systematic recording and analysis of suicides and suicide attempts to derive effective prevention strategies. In her new role, she can draw on the strong network in the field that exists in Frankfurt. One long-term goal is to establish a German Center for Suicide Prevention here. The position is funded by the Crespo Foundation, Henryk Sznap Stiftung, and the Dr. Elmar und Ellis Reiss Stiftung.

FRANKFURT. More than 10,000 people took their own lives in Germany last year, a figure that is more than three times as great as the number of traffic accident fatalities. The number of attempted suicides is significantly higher, affecting people across all age groups. Suicide studies focus on the factors that lead to suicide and its prevention. This important field is now receiving special attention in Frankfurt, where the first-ever German professorship for suicide studies and suicide prevention has been set up at 看片软件鈥檚 Faculty of Medicine.

Dr. Ute Lewitzka, who has been researching and working in this field for more than 25 years and currently serves as chair of the German Society for Suicide Prevention [Deutsche Gesellschaft f眉r Suizidpr盲vention], has been appointed to the position. 鈥淚鈥檓 very pleased to see suicide studies, which unfortunately still remain a niche topic, gain this level of recognition,鈥� says Lewitzka, who transitions to Frankfurt from Dresden University Hospital, adding that a professorship can help further destigmatize mental illnesses. Her goals include the systematic tracking and analysis of suicide attempts and suicides to further develop effective preventive measures and potentially also implement these at the political level.

The professorship is based at University Hospital Frankfurt's Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, headed by Prof. Andreas Reif, which has long specialized in treating mood disorders, such as depression. The goal is to establish a German Center for Suicide Prevention in collaboration with the German Foundation for Depression Relief and Suicide Prevention [Stiftung Deutsche Depressionshilfe und Suizidpr盲vention] and the European Alliance against Depression. A well-developed regional network already exists, uniting various stakeholders who drive research and treatment of suicidality and engage in prevention work, including school-based programs. Alongside research, specialist education and training are set to play a central role.

The project has secured funding for the next five years, thanks to the support of Crespo Foundation, Henryk Sznap Stiftung, and Dr. Elmar und Ellis Reiss Stiftung, with the latter contributing the majority of funds. Dr. Elmar Reiss, who set up the foundation with his wife in 2018, explained that the professorship鈥檚 goals align closely with the foundation鈥檚 mission: 鈥淥ur main goal in establishing the foundation was to help people with depression and alleviate their suffering. Depression is a condition that can increase suicide risk. Our foundation aims to help those affected find other paths and once again see light at the end of the tunnel.鈥�

Developing effective prevention methods requires an extensive amount of data. As part of a pilot project in Saxony, Lewitzka demonstrated that the prompt recording and evaluation of suicide attempts by specially trained emergency dispatchers enables the creation of 鈥渉eat maps鈥� that visually represent the locations and frequencies of incidents. Combined with targeted monitoring of the methods used in suicide (and suicide attempts), this approach can prevent many suicides. Frequently chosen methods of self-harm can be regulated 鈥� for instance, by controlling access to specific buildings or sites. 鈥淩estricting methods is one of the most effective prevention measures,鈥� Lewitzka explains.

About Prof. Dr. Ute Lewitzka
Born in 1972, Prof. Dr. med. Ute Lewitzka studied medicine in Berlin and Dresden and trained as a specialist in psychiatry and psychotherapy at Dresden鈥檚 Carl Gustav Carus University Hospital. Her doctoral thesis in 2004 and her habilitation in 2018 both focused on suicide studies. In 2017, she founded the Werner Felber Institute for Suicide Prevention and Interdisciplinary Research in Healthcare [Werner Felber Institut f眉r Suizidpr盲vention und interdisziplin盲re Forschung im Gesundheitswesen], of which she remains the chair. Since 2018, she has also served as volunteer chair of the Deutsche Gesellschaft f眉r Suizidpr盲vention (DGS) and the Suicide Studies Committee of the German Association for Psychiatry, Psychotherapy and Psychosomatics [Deutsche Gesellschaft f眉r Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde, DGPPN].

German Help Resources for Those Affected and Their Families
Frankfurt Suicide Prevention Network (FRANS):
Telephone Counseling Service: 1110111,
鈥淣ummer gegen Kummer鈥� (for children and youth): 116111,

Image for download:

Caption: Prof. Dr. Ute Lewitzka, 看片软件 Frankfurt (Photo: Maria Schlotte)

Further Information:
Prof. Dr. Ute Lewitzka
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy
University Hospital Frankfurt
lewitzka@med.uni-frankfurt.de

Nov 14 2024

13:20

Award ceremony honors long-standing sponsors聽

600 new Deutschlandstipendium scholarships at 看片软件

For the first time in six years, the number of Deutschlandstipendium scholarship holders at 看片软件 Frankfurt has reached the 600 mark again 鈥� thanks to the higher amount of donations received from private individuals, companies and institutions. On Wednesday, November 13, scholarship holders and sponsors met at a social get-together.

FRANKFURT. Students who are eligible for a Deutschlandstipendium scholarship must have good grades and display social commitment. Having been selected by jurors from the university's 16 faculties, they receive a monthly stipend of 鈧�300 for a maximum of two years to support their studies. This allows them to study more intensively, since they can spend less time financing their studies. Thanks to the state-funded scholarship program, this is now possible for 600 students 鈥� that's 50 more scholarship holders than in 2023. At 40 percent, the proportion of Deutschlandstipendium scholars with a migration background is also higher than in previous years.

At the annual award ceremony held on November 13, numerous scholarship holders collected their documents in person, and also met their sponsor. 650 students and sponsors filled the Casino building on 看片软件鈥檚 Westend Campus, whose stage was designed as a writing room, in keeping with the motto of Goethe's 275th birthday, and on which the evening unfolded like a literary program: In addition to 看片软件鈥檚 Schreibzentrum, which presented its services as well as the student-run literary magazine 鈥淛onny鈥�, university archivist PD Dr. Michael Maaser delivered a witty lecture.

Making two out of one: That is the principle according to which the Federal Ministry of Education and Research each year doubles the sum raised by 看片软件 for Deutschlandstipendium scholars. In 2024, a total of 鈧�1,080,000 was donated to 看片软件 by 250 private sponsors, 61 non-profit organizations and 50 companies 鈥� 鈧�35,000 more than in the previous year. After applying the federal government's matching principle, the scholarship holders had 鈧�2,160,000 at their disposal. Donations from non-profit organizations (NPO) have accounted for more than half of the total volume of Deutschlandstipendium funds raised by 看片软件 since the program was first set up in 2011.

Prof. Sabine Andresen, 看片软件鈥檚 Vice President Equal Opportunities, Career Development & Advancement, Diversity and Gender Equality honored the thirteen most loyal NPO and company sponsors at this year's award ceremony. In thanking them, she emphasized that their decision to invest financially and ideally in the education of young people and provide equal opportunities to students regardless of their background deserves the utmost respect. Turning to the sponsors, Andresen said: 鈥淚t is thanks to your active support that talented students can realize their full potential.鈥�

In addition to financial support, Deutschlandstipendium鈥檚 Young Leadership Program gives scholarship holders the opportunity to develop both personally and professionally. The range of services extends from individual support in project teams to study-related programs and offers, such as seminars, workshops, best-practice lectures, and networks. Together with fellow students from different faculties and degree programs, the scholarship holders work on innovative ideas in project teams, and are accompanied by non-university mentors.

Since 2011, 6,752 Deutschlandstipendium scholarships have been awarded at 看片软件 Frankfurt, corresponding to a funding amount of 鈧�12,153,600. According to the federal government's matching principle, 看片软件 students have received around 鈧�25 million through the Deutschlandstipendium to date.

Images for download:

Caption: The 600 students, who have received a Deutschlandstipendium scholarship at 看片软件 in 2024 have good grades and are socially engaged. This year, 361 private sponsors, non-profit organizations and companies donated a total of 鈧�1,080,000 to this cause (Photo: Uwe Dettmar/看片软件 Frankfurt)

Nov 12 2024

10:24

Newly discovered mechanism helps detach and recycle parts of cellular canal membranes as needed 鈥� models developed using supercomputer simulations

Bulges calculated in the supercomputer: How cells digest their internal canal system

Inside cells, there exists an extensive system of canals known as the endoplasmic reticulum (ER), which consists of membrane-encased tubes that are partially broken down as needed 鈥� for instance in case of a nutrient deficiency. As part of this process, bulges or protrusions form in the membrane, which then pinch off and are recycled by the cell. A study by 看片软件 Frankfurt has examined this protrusion process using computer simulations. Its finding: certain structural motifs of proteins in the ER membrane play a central role in this process. The study was carried out as part of the 鈥淪CALE - Subcellular Architecture of Life" cluster initiative.

FRANKFURT. The endoplasmic reticulum functions as a reservoir for calcium and carbohydrates and also serves as the site for the synthesis of various hormones. Cells adjust the expansion and networking of their internal canal system as needed. A process known as ER-phagy (鈥淓R-eating") plays a central role here. During this process, a part of the membrane of an ER tube bulges out and eventually pinches off into a small vesicle. At the same time, a kind of internal cellular 鈥渢rash bag", the autophagosome, forms around it. This then fuses with another container that contains highly reactive enzymes, which 鈥渟hred" the contents of the 鈥渢rash bag" and recycle it.

鈥淲e have known for several years that specific proteins, known as ER-phagy receptors, play a key role in this process," explains Dr. Ramachandra Bhaskara from 看片软件's Institute of Biochemistry II. These receptors are located in the membrane of ER tubes and consist of an anchor that inserts into the membrane. Attached to this anchor are two long protein strands that extend outward from the membrane surface like flexible tentacles. 鈥淯sing complex simulations in supercomputers, we were recently able to show, together with other research groups, that the anchor causes the membrane to curve," Bhaskara says, adding that 鈥渦nder certain conditions, this can result in a protrusion. In the current study, we have demonstrated that the filamentous structures increase the likelihood and significantly accelerate the formation of such a bulge."

Proteins form disordered 鈥渢entacles" from amino acids

Most proteins adopt a defined three-dimensional shape after they are produced: some parts form coiled, helical structures, while others fold back and forth like the bellows of an accordion. This gives them a compact, relatively rigid form, which also applies to the anchor region of ER-phagy receptors. The tentacles, however, consist of long chains of amino acids that oscillate back and forth in a largely disordered manner 鈥� which is also why they are referred to as 鈥渋ntrinsically disordered (protein) regions" or IDRs for short. These extensive movements require space, which they create by causing the membrane in which they are anchored to bulge. 鈥淎dded to this is another effect," emphasizes Dr. Sergio Alejandro Poveda Cuevas, the study's first author: 鈥淭he IDRs contain short sequences that can fold back under certain conditions. We were able to show that they do this during the formation of the bulges. They then nestle against the membrane like a scaffold, thereby reinforcing its curvature."

The pinching-off is thus the result of various finely orchestrated processes, as demonstrated by the simulation: initially, the anchor regions of various ER-phagy receptors approach each other. This clustering increases the curvature of the membrane caused by the receptors. Initially, the IDR tentacles are extended. They make contact with the autophagy machinery and direct it toward the membrane. The IDRs then condense into more compact structures, further enhancing the bulge until the membrane pinches off and the vesicle is packaged in the autophagosome (鈥渢rash bag").

Findings could prove important for the treatment of certain diseases

鈥淚n addition to offering a detailed insight into this important cellular process, our study also shows that receptor IDRs play a crucial role in ensuring smooth functioning," Bhaskara explains. These results are particularly interesting because some congenital neurological diseases are associated with disrupted ER-phagy. A better understanding of the membrane degradation process might one day enable targeted manipulation.

The study was funded by the German Research Foundation (DFG) within the framework of Collaborative Research Center 1177, and by the ENABLE cluster project funded by the Hessian Ministry of Science and Research, Arts and Culture.

Publication:
Sergio Alejandro Poveda-Cuevas, Kateryna Lohachova, Borna Markusic, Ivan Dikic, Gerhard Hummer, Ramachandra M. Bhaskara: Intrinsically disordered region amplifies membrane remodeling to augment selective ER-phagy. PNAS (2024)

Movie/Image for download:
Image sequence:
Movie (19 MB):

Caption (image and movie): The ER-phagy receptor FAM134B is initially distributed via the membrane surface (left). Its IDRs move back and forth in a largely disordered manner, like tentacles. The formation of local clusters initiates the curvature of the membrane (2nd from left), which is further strengthened by the condensation of the tentacles into more compact structures (2nd from right). The pinching off of the membrane vesicle (not shown) is initiated by a targeted redistribution of proteins (sorting, right). Image: Bhaskara Group, 看片软件 Frankfurt

Further information
Dr. Ramachandra M. Bhaskara
Head of 鈥淐omputational Cell Biology" working group
Institute of Biochemistry II
看片软件 Frankfurt
Tel.: +49 (0) 69 6303-2508
bhaskara@med.uni-frankfurt.de
Homepage:

Twitter/X: @goetheuni @IBC2_GU @RamBhaskara4 @HummerLab @DikicLab @EnableFrankfurt @sfb1177 @SCALE_Uni_FFM @MPIbp

Nov 6 2024

16:08

鈥淧oetics of Rhythm鈥�: German Research Foundation (DFG) funds Reinhart Koselleck Project by Professor Achim Geisenhansl眉ke聽

Rhythm as 鈥渇orm in motion鈥� and its significance for poetics

What is the significance of rhythm for poetics? Literary studies research has not yet answered this question exhaustively. Professor Achim Geisenhansl眉ke wants to change this. He will work on the poetics of rhythm within a Reinhart Koselleck Project funded by the German Research Foundation (DFG).

FRANKFURT. 鈥淧oetics of Rhythm" 鈥� that is the title of a project currently in the starting blocks at 看片软件 Frankfurt. The aim of Professor Achim Geisenhansl眉ke, Professor for Literary Theory and Comparative Literature, is to unfold the possibilities of a poetics of rhythm, which have not yet been fully exploited by literary studies, both systematically and historically. He combines the question of the fundamental significance of rhythm for the theory and practice of poetry (= poetics) with that of concrete manifestations of this phenomenon in poetry from modernity to the present day.

At the heart of the research work is rhythm in poetry. Is rhythm in poetry not simply meter? Not at all, says Achim Geisenhansl眉ke. Although rhythm also describes 鈥渇orm in motion" in poetic speech, it is far more encompassing than the concept of meter. Especially with regard to modern poetry, the potential offered by the concept of rhythm has so far hardly been studied. In his approach, Geisenhansl眉ke is above all continuing the work of Henri Meschonnic (1932-2009), the French poet, linguist and literary scholar who induced an upward revaluation of the concept of rhythm as part of a critical analysis of structuralist and post-structuralist literary theories.

Achim Geisenhansl眉ke's project will approach the topic in three sub-studies: The first will focus on rhythm in the poems of Friedrich H枚lderlin, the second will critically examine Foucault's theory of discourse and Meschonnic's theory of rhythm, while the third sub-study is dedicated to rhythm as 鈥渇orm in motion" in modern poetry up to the present day, from Annette von Droste-H眉lshoff and Charles Baudelaire to Thomas Kling.

The financial support from the German Research Foundation (DFG) allows the freedom needed to pursue all these aspects. The project will receive 鈧�750,000 in increments spread over five years, which can be distributed flexibly for teaching replacements, recruiting staff, assistants, workshops and conferences.

The funding line, which has existed since 2008, is named after Reinhart Koselleck (1923-2006), one of the most important German historians of the 20th century, who is considered a co-founder of modern social history. Reinhart Koselleck Projects are awarded to 鈥渙utstanding researchers with a proven scientific track record". The prerequisites for approval are exceptionally innovative approaches or a higher degree of risk.

In the case of Achim Geisenhansl眉ke's project, the risks lie in the attempt, within a comparative approach, to take rhythm, a concept that is as central to literary studies as it is underestimated, and use it to give poetics new impetus: No risk, no gain.

A portrait photograph of Professor Achim Geisenhansl眉ke is available for download at: https://www.puk.uni-frankfurt.de/160017255

Caption: Within a Reinhart Koselleck Project, Professor Achim Geisenhansl眉ke is examining the role of rhythm as a concept in literary theory. (Photo: Uwe Dettmar)

Further information
Professor Achim Geisenhansl眉ke
Department of Literary Theory and Comparative Literature
Faculty of Modern Languages
看片软件 Frankfurt
Tel. +49 (0) 69 798-32869
gei senhanslueke@lingua.uni-frankfurt.de