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Chaperones disassemble Parkinson’s disease-specific amyloid fibrils

Amyloid fibrils consisting of clumped α-synuclein protein are characteristic of Parkinson's disease. Chaperones, which ensure the correct folding of newly synthesised polypeptides, can inhibit α-synuclein aggregation and, as a consequence, prevent fibrils from forming. Researchers from Heidelberg have shown that a specific combination of human molecular chaperones is able to disassemble fibrils and transform them into non-toxic α-synuclein monomers. This mechanism has the potential to open up new pathways for developing drugs for treating Parkinson's disease.

Prof. Dr. Bernd Bukau from the ZMBH, which is jointly run by Heidelberg University and the DKFZ © Bukau, ZMBH

Many neurodegenerative diseases are characterised by amyloid fibrils, i.e. fibrous protein deposits in nerve cells of the brain. The amyloidogenic proteins from which these fibrils are formed include, for example, the amyloid beta and Tau proteins that are the hallmarks of Alzheimer's disease and the α-synuclein protein involved in the pathogenesis of Parkinson's disease. Both diseases usually appear only in older people, which suggests that there is a mechanism in the nerve cells that prevents amyloid formation at a young age. Although there are also hereditary forms of Alzheimer's and Parkinson's disease that are caused by mutations and break out at a relatively early age, the amyloidogenic proteins even in these hereditary disease forms are in a latent state for many years before disease symptoms can eventually be detected. The aggregation of several misfolded protein molecules into oligomers represents the intermediate stage of fibril formation. It seems that it is not only the fibrils, but also the oligomers that are toxic for nerve cells.

Disaggregase disassembles amyloid fibrils

Special cellular components are essential for the correct three-dimensional folding of amino acid chains into functional proteins as well as for the correction and, if necessary, elimination of proteins when folding errors occur. These components are called molecular chaperones.1 So-called heat shock proteins (Hsp), including the Hsp70 protein family, are the best-known chaperone group. A complex system of chaperones (French for a woman who supervises young people at social occasions) and chaperone-associated components that target α-synuclein and other amyloidogenic proteins and prevent their aggregation into fibrils is already known. However, neural α-synuclein proteins that have already formed fibrils seem to be largely resistant to chaperone disassembly.

Electron microscope image of α-synuclein fibrils that are fragmented by chaperones. © Bukau, ZMBH

In a large-scale study, however, the Heidelberg molecular biologist Prof. Dr. Bernd Bukau and his team were able to demonstrate that components of the Hsp70 chaperone system form an effective “disaggregase”, which cuts α-synuclein fibrils into short fragments and subsequently depolymerises them into non-toxic protein monomers. The paper written by Bukau and his team and published in the scientific journal “Molecular Cell” in 2015, studied amyloid fibrils that formed in vitro by polymerising α-synuclein proteins and cell-free human neuroblastoma cell extracts. Using various chromatographic, immunobiochemical and electron microscope methods, the researchers’ comprehensive investigations at the Centre for Molecular Biology at the University of Heidelberg (ZMBH) and the German Cancer Research Center (DKFZ) led to the discovery of a mechanism that enables the interaction of three Hsp70 components (the protein DNAJB1, the Hsc70 chaperone and the nucleotide exchange factor APG2) with the fibrils. The binding of these components to the toxic α-synuclein fibrils in several consecutive cycles is an ATP-dependent process that generates the power stroke required for the fragmentation and depolymerisation of the fibrils into non-toxic monomers.

Schematic representation of a mechanism leading to the fragmentation of amyloid fibrils.
Schematic representation of a mechanism that enables three components of the human disaggregation machinery (DNAJB1, Hsc70 und Apg2) to fragmentise α-synuclein amyloid fibrils. © Bukau, ZMBH

Research project funded by Baden-Württemberg Stiftung

The discovery of a human Hsp70 disaggregase complex that can disassemble amyloid fibrils characteristic of Parkinson’s disease, sheds new light on the mechanisms that might play a role in the pathogenesis and control of Parkinson’s disease. These findings also have the potential to open up new possibilities in the search for effective medications to prevent this feared neurodegenerative disease. In Germany alone, Parkinson’s affects between 250,000 and 400,000 people, for whom cure is currently no more than a vague hope. Bernd Bukau and his team have now received funding from Baden-Württemberg Stiftung, which is one of the major foundations in Germany, for further research on the disaggregase complex and the dissolution of the α-synuclein fibril complexes. Funding will be provided for a period of three years under the "International Cutting-edge Research III" programme.2 As part of the project, which is entitled "Mechanism of α-synuclein amyloid fibril disaggregation by molecular chaperones”, the Dutch scientist Dr. Anne Wetink from Bukau’s laboratory will study the three-dimensional structure of α-synuclein amyloid in Parkinson’s disease using biochemical and structural biology methods.

Bernd Bukau explained: "We believe that detailed knowledge of the binding mechanisms will provide us with insights into the cell’s potential to counteract protein aggregation, and enable us to come up with new approaches for the development of drugs for treating Parkinson’s.” As in the discovery of the Hsp70 disaggregase, the team from Heidelberg is once again working with Prof. Dr. Helen R. Saibil from the Department of Crystallography at the University of London. The Canadian-British structural biologist, who has made a name for herself for research into chaperones and protein misfolding, will study the binding of the disaggregase components to the α-synuclein fibrils using electron microscopy methods and make them visible with a nanometer range resolution.

Chaperone researchers

Prof. Dr. Bernd Bukau, molecular biologist and biochemist, and his colleagues are among the leading researchers worldwide in the field of chaperones and the cellular machinery that is responsible for the quality control of proteins. Bernd Bukau is director of the Centre for Molecular Biology at the University of Heidelberg (ZMBH), where he heads up the “Biogenesis and quality control of proteins” laboratory. Bukau also heads up the Division of Chaperones and Proteases at the German Cancer Research Center (DKFZ). He was one of the initiators and co-director of the DKFZ-ZMBH Alliance, a strategic cooperation of the DKFZ’s Cell Biology and Tumour Biology research priority and the ZMBH, where around 30 research groups involving more than 400 international scientists work together on basic cell and molecular biology research. Bukau is a member of the European Molecular Biology Organisation (EMBO), the National Academy of Sciences Leopoldina and the Heidelberg Academy of Sciences. For his research in the field of chaperones, Bukau was awarded the Leibniz Prize of the German Research Foundation, the Leopoldina Research Prize and the Heidelberg Molecular Life Sciences Award. This year, Bukau received a competitive "ERC Advanced Grant" from the European Union for a future research project in this field.

Original publication:

Gao X, Carroni M, Nussbaum-Krammer C, Mogk A, Nillegoda NB, Szlachcic A, Guilbride DL, Saibil HR, Mayer MP, Bukau B: Human Hsp70 disaggregase reverses Parkinson’s-linked α-synuclein amyloid fibrils. Molecular Cell 59, 781-793 (2015). http://dx.doi.org/10.1016/j.molcel.2015.07.012

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/chaperones-disassemble-parkinsons-disease-specific-amyloid-fibrils