2.5 Million Euros for Research into the Neurological Diseases ALS and FTD

Prof. Dieter Edbauer, a neuroscientist at DZNE’s Munich site, has been awarded an Advanced Grant by the European Research Council (ERC), securing 2.5 million euros to investigate the molecular mechanisms of two devastating neurological diseases: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). His research project focuses on inherited forms of these diseases due to mutations in a gene called C9orf72 and on flawed DNA repair mechanisms. With these studies, Edbauer hopes to pave the way for novel treatment strategies.

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,” explains Dieter Edbauer, a DZNE research group leader.

Failed repair

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 the neuroscientist, who is also a member of the Munich-based SyNergy Cluster of Excellence and a professor at LMU Munich.

Genomically unstable

The DNA is very fragile: Thus, sophisticated molecular repair mechanisms swiftly eliminate accidental damage to protect cells from cancer. If the repair fails, the affected cells activate a suicide program. In neurons, this may trigger neurodegeneration. Edbauer suspects that this is exactly what is happening here. “The altered C9orf72 gene is a hotspot for repair processes. This could be triggered by transcription of the repeats.” So-called “transcription”, a standard process in cell metabolism, involves making a molecular copy of genetic information. For this to happen, the two strands that comprise the DNA molecule must be separated. However, when they are joined together later, the individual parts may slip out of place due to the repeats in the genetic code. This leaves bulges in the DNA, similar to what happens in an incorrectly closed zipper. “I suspect that the subsequent repair processes make the situation worse. Ultimately, this region of the genome is prone to errors and unstable. This could result in neuron death,” Edbauer says.

Prospects

Edbauer’s team will investigate these repair processes and their presumably fatal consequences by studying cell cultures, mice and patient samples. “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.”

_{June 2025}