Biologists study how molecular chaperones dissolve protein aggregates linked to Parkinson’s

Reviewed by Emily Henderson, B.Sc.November 11, 2020

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

Molecular biologists from the University of Heidelberg and the German Cancer Research Center have studied how the Hsp70 system breaks down Parkinson’s-specific protein α-synuclein amyloid fibrils in a test tube. The research team led by Prof. Dr Bernd Bukau expects the research results to provide new insights into how Parkinson’s disease develops and what could be done to affect it. The findings were published in two articles in the journal Nature.

The proteins in all cells, from bacteria to humans, must fold to their native state. The amino acid block chains take on specific three-dimensional structures that give proteins their functionality. This state of correct folding is constantly threatened by external and internal influences which can lead to incorrectly folded and thus damaged proteins. There is a risk that the damaged proteins “clump” or clump into longer strands, the amyloid fibrils. This happens with α-synuclein in Parkinson’s disease, for example. The fibrils, in turn, are the starting point for even larger deposits.

The process of formation of these fibrillar aggregates can damage cells and even lead to cell death, as in the case of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. ”

Prof. Bernd Bukau, researcher, Heidelberg University Molecular Biology Center (ZMBH) and German Cancer Research Center (DKFZ)

Prof. Bukau’s research focuses on how these protein aggregates can be dissolved. In previous work, he and his team were able to identify cellular activity that plays a vital role in the dissolution of fibrillar aggregates, which relies on Hsp70 family chaperones. Hsp70 chaperones help other proteins fold and can even isolate and fold aggregate proteins. The latest research by Prof. Bukau and Dr Anne Wentink shows the effects that Hsp70 chaperones have on Parkinson’s specific amyloid fibrils of the α-synuclein protein. Α-synuclein is a small protein that helps in the release of messengers called neurotransmitters in the brain, although its exact function remains unclear. It became known why massive deposits of this specific protein were found in Parkinson’s patients and it was causally linked to the disease.

In biochemical experiments, Heidelberg scientists were recently able to show that the human chaperone Hsp70 relies on the assistance of two specific co-chaperone partners to dissolve the amyloid fibrils of the α-synuclein protein. A precisely regulated interaction of these proteins leads to the formation of chaperone complexes on the surface of the fibrils, which then break down the aggregates. “It is the sheer local accumulation of many chaperone proteins on the surface of the α-synuclein fibrils that generates the force to break the fibrils and detach the α-synuclein molecules,” explains Dr. Wentink. The close proximity between the chaperones on the narrow surface of the fibrils plays a decisive role in creating tensile forces strong enough to disrupt the fibrils.

The experiments were conducted together with colleagues from the European Molecular Biology Laboratory (EMBL) in Heidelberg, the Center for Structural Biology in Montpellier (France) and the École Polytechnique Fédérale 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.

The second study published in Nature focuses on a previously unknown regulatory mechanism, a type of molecular switch that sets in motion the overall activity of chaperone Hsp70 to dissolve amyloid fibrils. This mechanism is based on a sequence of direct interactions between the different parts of the DNAJB1 co-chaperone and the Hsp70 chaperone. This ultimately activates the Hsp70 to use ATP as an energy source, making it possible for productive binding to the fibrils and their disintegration. A close research collaboration of Dr. Rina Rosenzweig of the Weizman Institute of Science in Rehovot (Israel) and Prof. Bukau, Dr. Wentink and Dr. Nadinath Nillegoda of Monash University in Melbourne (Australia) – former fellow of the Foundation Alexander von Humboldt in the research of Bernd Bukau group – managed to identify this mechanism.

“Our latest results from the two studies give us a molecular understanding of how amyloid fibrils dissolve. We were able to show that chaperones work as a fibril-dissolving machine,” adds Prof. Bukau.

According to the Heidelberg researcher, this opens up new avenues for the development of agents that specifically target the chaperone-based cell defense mechanism against amyloid formation. A better understanding of how this chaperone activity affects the course of neurodegenerative diseases will therefore be of fundamental importance in the therapeutic exploitation of the results described in these studies.