Biologists investigate how molecular chaperon dissolves protein aggregates associated with Parkinson’s disease

Review by Emily Henderson, Bachelor of ScienceNovember 11, 2020

In many neurodegenerative diseases such as Parkinson’s disease, protein aggregates are thought to form in the brain and contribute to neuronal cell death. However, there is a cell defense mechanism that counteracts these aggregates known as amyloid fibrils, which can even lyse already formed fibrils. This defense mechanism is based on the activity of the molecular chaperones of the heat shock protein 70 family (Hsp70), the protein folding helpers.

Molecular biologists at the University of Heidelberg and the German Cancer Research Center investigated how the Hsp70 system degrades amyloid fibrils of the Parkinson-specific protein α-synuclein in vitro. The research team, led by Professor Bernd Bukau, hopes that their findings will provide new insights into how Parkinson’s disease develops and what can be done to influence it.The results were published in two articles in the journal Nature..

Proteins from all cells, from bacteria to humans, need to fold into their original state. The chains of amino acid building blocks envision specific three-dimensional structures that give function to proteins. This correct folding condition is always threatened by external and internal effects that can cause accidental folding and protein damage. There is a risk that the damaged protein will “aggregate” or aggregate into longer strands of amyloid fibrils. This happens, for example, with α-synuclein in Parkinson’s disease. Fibril, in turn, is the starting point for larger sediments.

The process of forming such fibrous aggregates can damage cells and even lead to cell death, as in neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. ”

Professor BerndBukau, a researcher at the Center for Molecular Biology (ZMBH) and the German Cancer Research Center (DKFZ) at the University of Heidelberg

Professor Bukau’s work focuses on how these protein aggregates can be dissolved. In a previous study, he and his team succeeded in identifying cellular activity that plays an important role in the lysis of chaperone-based fibril aggregates in the Hsp70 family. The Hsp70 chaperone helps fold other proteins and can even separate and refold aggregated proteins. A recent study by Professor Bukau and postdoctoral fellow Ann Wentink shows the effect of Hsp70 chaperones on Parkinson-specific amyloid fibrils of the α-synuclein protein. Alpha-synuclein is a small protein that helps release messengers called neurotransmitters in the brain, but its exact function remains unknown. Large deposits of this particular protein have been found in patients with Parkinson’s disease and have become known for their causal link to the disease.

In biochemical experiments, Heidelberg scientists have recently been able to show that human Hsp70 chaperones rely on the support of two specific co-chaperone partners to lyse the amyloid fibrils of the α-synuclein protein. I did. The precisely controlled interactions of these proteins form a chaperone complex on the surface of the fibril, which breaks down aggregates. “It is the local accumulation of many chaperone proteins on the surface of the α-synuclein fibrils that destroys the fibrils and creates the force to separate the α-synuclein molecules,” explains Dr. Wentink. The proximity between chaperones on the restricted surface of the fibril plays a decisive role in creating a pulling force strong enough to destroy the fibril.

The experiment was conducted with colleagues from the European Molecular Biology Laboratory (EMBL) in Heidelberg, the Structural Biology Center in Montpellier (France), and the Ecole Polytechnique Federal de Lausanne (Switzerland). The project was funded by the “Top Research” program of the Baden-Württemberg Foundation, the German Research Foundation and the Helmholtz Association.

Second study published in Nature It focuses on a previously unknown regulatory mechanism, a type of molecular switch that drives overall Hsp70 chaperone activity to lyse amyloid fibrils. This mechanism is based on a series of direct interactions between different parts of the DNAJB1 co-chaperone and the Hsp70 chaperone. This will eventually activate Hsp70, allowing ATP to be used as an energy source and productively bind to fibril, resulting in their decay. Close collaboration between Dr. Lina Rosenzweig of the Weizmann Institute of Science in Rehovot (Israel) and Dr. Bukau, Dr. Wentink, and Dr. Nadinas Nirgoda of Monash University in Melbourne (Australia)-former Alexander in Bernd Bukau’s work Fellow Group of the von Humboldt Foundation-Successfully identified this mechanism.

“The latest results from the two studies provide a molecular understanding of how amyloid fibrils dissolve. Demonstrate that chaperones act like machines that dissolve fibrils. We’ve done that, “adds Professor Bukau.

According to Heidelberg researchers, this opens new avenues for the development of drugs that specifically target chaperone-based cell defense mechanisms against amyloid formation. Therefore, a better understanding of how this chaperone activity affects the course of neurodegenerative disease is essentially important in the therapeutic use of the findings described in these studies.