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Lecture

Reedijk Symposium 2022: Untangling protein aggregates in neurodegenerative disease

Date
Friday 28 October 2022
Time
Location
Gorlaeus Lecture Hall Building (collegezalengebouw), Einsteinweg 57
Room
Lecture Hall 1

Abstract

Protein aggregation into amyloid fibers is a hallmark of debilitating neurodegenerative diseases including Parkinson's disease (PD). These highly ordered and stable fibrillar aggregates are challenging substrates to the cellular protein quality control machinery. It is therefore surprising that the human Hsp70 chaperone can not only prevent protein aggregation but in fact dissolve preformed fibers of PD-linked α-synuclein.

Using a combination of NMR spectroscopy and biochemical techniques, we have reconstituted key steps of the ATP dependent disaggregation process to describe the molecular mechanism of this unique biological activity. We uncovered a novel level of cooperation between Hsp70 co-chaperones that facilitates the assembly of dense Hsp70 complexes close to the amyloid surface, ideal for the generation of "entropic pulling" forces that result in disaggregation.

Our experiments however also uncovered a potentially harmful side to the disaggregation process. As Hsp70 clears amyloid fibres, it also break fibrils down into smaller fragments. These fragments have the ability to act as conformational template, thus promoting further aggregation. Hsp70 mediated disaggregation thus, inadvertently, can create a negative feedback loop that accelerates protein aggregation, the infection of neighbouring cells and may even drive, rather than prevent disease.

Biography

Dr. Anne S Wentink (09-05-1990) studied Biochemistry at University College London (UCL) from 2007-2010. She obtained a BBSRC scholarship to pursue a PhD in the lab of Prof John Christodoulou at UCL (2010-2015). Here she used solution-state NMR spectroscopy to study the structure and dynamics of the ribosome associated bacterial chaperone Trigger Factor and its interaction with nascent polypeptide chains.

Her postdoctoral research with Prof Bernd Bukau at Heidelberg University (since 2015) on the molecular mechanism of amyloid fibre disaggregation by the human Hsp70 chaperone cumulated in two back-to-back publications in Nature in 2020. In January 2022, she started her own research group as assistant professor within the division of Macromolecular Biochemistry focused on understanding the role of chaperone mediated disaggregation of protein aggregates in the context of neurodegenerative disease.

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