University of Bremen: New insights into Huntington’s disease

Huntington’s disease is an inherited disease that leads to cognitive and motor impairment and death. Scientists from the University of Bremen and international partners have elucidated the mechanism by which the mutated huntingtin protein can be kept in check.
“We have elucidated a mechanism with which so-called endogenous protein folding helpers keep the mutant huntingtin protein in check,” explains project manager and professor Janine Kirstein from the University of Bremen. Protein folding facilitators allow proteins to assume and maintain their proper structure to perform their multiple functions. The researchers already knew three of the protein folding assistants. But what they didn’t know yet: How does the binding with the mutated huntingtin look likeprotein exactly? Which of the three folding helpers does the mutated protein recognize and how does the binding work? “We have now been able to identify this using the crosslinking mass spectrometry method,” says the biochemist. Protein interactions can be precisely determined with the method. However, there was still a long way to go to understand the bond. “It was only through modeling that we were able to better understand the interaction between protein folding helpers and mutated huntingtin.”

Research success through practiced interdisciplinarity
The success of these new findings is lived interdisciplinarity: “The fact that we were able to obtain our results so precisely was mainly due to the very good cooperation between the departments of biology/chemistry and production engineering at the University of Bremen,” says Janine Kirstein We need researchers for our project who can support us in our experimental laboratory work with computer-aided models.” Janine Kirstein’s doctoral student Yasmin Richter found the necessary engineering expertise in her former fellow student of the Biochemistry & Molecular Biology master’s program , Isabell Grothaus. Isabell Grothaus is doing her PhD in the group of Dr. Susan Koppen and Professor Lucio Colombi Ciacchi. This is how the two young scientists created a cooperation between the two departments. “The engineers simulated the binding between the protein folding helpers and the mutated huntingtin protein on the computer for us, and we were then able to experimentally validate the models in our laboratory with purified proteins and in cell cultures,” explains Janine Kirstein.

Another hurdle was the previously unknown structure of the mutated huntingtin protein. The cooperation partners Martin Kulke and Josh Vermaas from Michigan State University in the USA were able to help out here, postulating a structure with which the modeling could be carried out on the computer. Another important cooperation partner was Fan Liu for the mass spectrometric experiments at the Leibniz Research Institute for Molecular Pharmacology in Berlin, where Janine Kirstein was a research group leader until 2019 before she was appointed to the University of Bremen.

Build on the research results
“With this work, we have succeeded in understanding the mechanism by which a protein folding helper selectively recognizes a mutated disease-associated protein and renders it harmless. This alone is not sufficient for therapeutic use,” says Janine Kirstein. “But you can build on these results and develop strategies to specifically induce or stabilize these endogenous folding helpers in order to suppress the toxicity of mutant huntingtin .”

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