Three SyNergy members receive ERC Advanced Grant
Dieter Edbauer
ALS and FTD are neurodegenerative diseases with severe consequences and ultimately fatal outcome: ALS causes progressive paralysis, while FTD leads to behavioral changes and speech disorders. Current therapies can alleviate some effects, but there is currently no cure. In addition, there are mixed forms with overlapping symptoms. Many cases in this spectrum of diseases are genetic, with remarkable similarities in the genome. Most of these cases are due to mutations in a gene called C9orf72. In these patients, a short DNA sequence is repeated hundreds or thousands of times. Edbauer and colleagues previously discovered that these “repeats” lead to the creation of toxic proteins. “We are collaborating with an industry partner to develop a vaccine against these harmful molecules. Our research points to an additional disease mechanism. Specifically, I suspect that the body’s own DNA repair mechanisms, aimed at protecting against cancer, backfire, ultimately worsening damage and triggering neuron loss. I am excited to pursue this novel direction with the ERC funding,” says Edbauer. His team will investigate these repair processes and their presumably fatal consequences: “I expect this project to provide insights into the mechanisms of ALS and FTD with C9orf72 mutation and to open up new avenues for therapy. However, I also hope to gain insights into other neurological diseases,” says Edbauer. “Repeats in the genome also occur in over 50 other diseases such as Huntington’s disease. Findings from our project may have broad significance for the mechanistic understanding and therapy of such repeat expansion disorders.”
Dieter Edbauer is a Professor of Translational Neurobiochemistry at LMU and neuroscientist at DZNE’s Munich site.
>> Read more about his ERC Advanced Grant Research project on the website of DZNE
Thomas Korn
The thymus gland functions like a school for T cells. Here, progenitors to immune cells that could later attack the body’s own tissues are eliminated. Thomas Korn and his team have discovered that B cells, another type of immune cell, play a role in this process. They present autoantigens – molecules that originate from the body itself – to developing T cells. In doing so, they help ensure that any T cells that misidentify these molecules as threats are removed. If this process goes awry, autoimmune diseases can develop – such as neuromyelitis optica, in which the autoantigen AQP4 is mistakenly recognized as a threat. In the research project BREAKING BAD, Thomas Korn and his team aim to investigate these mechanisms in greater detail. In particular, the researchers want to find out whether similar failures might cause T-cells to proliferate, which misclassify the autoantigen amyloid precursor protein (APP) as a threat. This could offer a possible explanation for the development of diseases like Alzheimer’s. If these processes could be influenced, entirely new possibilities might emerge for diagnosis and the development of novel therapies.
Thomas Korn is Professor of Experimental Neuroimmunology at Klinikum der Technischen Universität München (TUM Klinikum).
>> Read more about his ERC Advanced Grant Research project on the website of TUM
Christian Weber
Atherosclerosis is the principal cause of cardiovascular diseases, which remain the leading cause of death worldwide. Christian Weber has demonstrated that a microRNA fragment called miR126-5p can protect against atherosclerosis by binding to and inhibiting the enzyme Caspase-3 in the cell nucleus, which otherwise confers programmed cell death. Weber has thus discovered a completely new function of microRNAs, which had generally been assumed to operate in the cytoplasm by suppressing or degrading messengerRNAs in a silencing complex. The new signaling pathway is mediated by the RNA-binding protein MEX3A, which will now be the focus of Weber’s ERC project MONOFUN-CV.
In his project, Weber takes MEX3A as the starting point to systematically investigate these newly discovered non-canonical miRNA mechanisms together with his team. Their goal is to explore the cell-specific role of MEX3A in atherosclerosis in a mouse model and by analogy identify genetic risk variants in humans. By using various screening methods, the researchers aim to find other miRNAs that functionally require MEX3A as well as other proteins directly regulated by miRNAs, and they further plan to elucidate the structural mechanisms underlying the functions of MEX3A. Other goals of the project include analyzing the direct interactions between miR-126-5p and Caspase-3 – including their biological relevance in vivo – and the systematic quest for functional miRNA-protein pairs, which could serve as a template for novel RNA-based therapeutics.
In the long term, these findings could yield new insights into the non-canonical mechanisms of miRNAs and open up novel therapeutic approaches – for cardiovascular diseases and beyond.
Christian Weber serves as the Director of the Institute for Cardiovascular Prevention at LMU University Hospital, where he is Chair and Professor of Vascular Medicine.
>> Read more about his ERC Advanced Grant Research project on the website of the LMU