Hsp70 chaperones dissolve protein aggregates in Parkinson’s disease

Significance 

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

Molecular biologists from Heidelberg University and the German Cancer Research Center investigated how the Hsp70 system disaggregates amyloid fibrils of the Parkinson-specific protein α-synuclein in a test tube. The research team led by Dr. Bernd Bukau expects their research results to provide new insights into how Parkinson’s disease develops and what might be done to influence it. The results were published in in the prestigious journal Nature.

Proteins in all cells, from bacteria to human cells, need to fold to their native state. The chains of amino acid building blocks assume specific three-dimensional structures that give proteins their functionality. This state of correct folding is constantly threatened by external and internal influences that can lead to incorrectly folded and hence damaged proteins. There is a risk that damaged proteins will aggregate, or clump together 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 formation process of such fibrillar aggregates can damage cells and even lead to cell death, as is the case in neurodegenerative diseases like Parkinson’s and Alzheimer’s.  Dr. Bukau research focuses on how these protein aggregates can be dissolved. In earlier work, he and his team succeeded in identifying a cellular activity that plays a vital role in dissolving fibrillar aggregates, which is based on chaperones of the Hsp70 family. Hsp70 chaperones help other proteins with folding and can even isolate and refold aggregated proteins. The latest research by Heidelberg University researchers shows the effects the Hsp70 chaperones have on the Parkinson-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 because massive deposits of this specific protein were found in Parkinson’s patients and has been causally linked to the disease.

In a series of elegant biochemical experiments, the Heidelberg scientists were recently able to show that the human Hsp70 chaperone 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 up the aggregates. Indeed It is the sheer local accumulation of many chaperone proteins on the surface of the α-synuclein fibrils that generates the force to break up the fibrils and detach the α-synuclein molecules. The close proximity between the chaperones on the restricted surface of the fibrils plays a decisive role in creating strong enough pulling forces to disrupt the fibrils. A subsequent second paper by the same research team was also published another paper in Nature, and focused on a previously unknown regulatory mechanism, a type of molecular switch that sets in motion the overall Hsp70 chaperone activity to dissolve the 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 Hsp70 to use ATP as an energy source, making it possible to productively bind to the fibrils and effect their disintegration.

The new findings advances our molecular understanding of how amyloid fibrils are dissolved. They were able to demonstrate that the chaperones work like a machine to dissolve the fibrils. According to the authors, this opens up new avenues for the development of agents that specifically target the chaperone-based cellular defense mechanism against amyloid formation. A better understanding of how this chaperone activity influences the course of neurodegenerative diseases will thus be of essential importance in the therapeutic exploitation of the findings described in these studies.

Hsp70 chaperones dissolve protein aggregates in Parkinson's disease - Medicine Innovates
Figure Legend: Disaggregation of α-synuclein amyloid fibrils relies on the cooperation of the HSP70 chaperone with its co-chaperones DNAJB1 and HSP110. This cooperation ensures recognition of the fibrils, followed by the correct assembly of the Hsp70 disaggregase machinery on the fibril surface thereby allowing for productive disaggregation. Credit: Bernd Bukau / Heidelberg University

About the author

Professor Bernd Bukau

He is the ZMBH Research Group Leader & DKFZ Division Head.  Professor Bukau research interest is in studying mechanisms of folding and assembly of newly synthesized proteins: Cells from bacteria to humans have evolved a multilayered machinery that engages translating ribosomes to promote folding and assembly of newly synthesized proteins. Using ribosome profiling, genetics and protein biochemistry, we want to understand how this machinery guides nascent polypeptides to the native state, and how assembly of oligomeric protein complexes is achieved in pro- and eukaryotes.

Professor Bukau is interested to elucidate the mechanisms of protein quality control:  Disrupting proteostasis of living cells activates protective quality control systems, which refold or degrade misfolded proteins or sequester potentially cytotoxic misfolded proteins into aggregates, deposited at specific intracellular sites. We want to understand the cellular processes leading to targeted deposition of aggregating proteins inside cells. We are also dissecting the mechanisms by which the Hsp70 chaperone network and the AAA+ disaggregase Hsp104 solubilize and refold aggregated proteins, including disease-associated amyloid fibrils.

He also  has active research in propagation of protein misfolding in neurodegenerative diseases:  neurodegenerative diseases exhibit a complex pathology involving non-cell autonomous effects and progressive spreading of protein misfolding. Using the metazoan model system C . elegans we want to understand how local protein misfolding is affecting neighboring cells and tissues and how proteostasis is orchestrated at the organismal level.

Reference

Ofrah Faust, Meital Abayev-Avraham, Anne S. Wentink, Michael Maurer, Nadinath B. Nillegoda, Nir London, Bernd Bukau & Rina Rosenzweig. HSP40 proteins use class-specific regulation to drive HSP70 functional diversity. Nature volume 587, pages489–494(2020)

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