Biological Sciences

Events and seminars

CANCELLED: Monday Seminar Series - "Cellular protein aggregation and disaggregation by chaperones"

Professor Helen Saibil - Department of Biological Sciences, Birkbeck, University of London

23rd March 2020 at 12:15pm [Download iCalendar / .ics file]

Daniel Rutherford Building, G.27, Lecture Theatre

Protein misfolding leading to aggregation, whether due to mutations or to sporadic events in ageing, is associated with fatal degenerative diseases, including neurodegeneration. The nature of the cytotoxic species remains obscure, despite common features appearing in a wide range of misfolding diseases. There is typically a latent period during which protein aggregates begin to accumulate, often in the form of amyloid fibres with a well defined cross-beta core, and the eventual appearance of pathology and cell death.

 

We have used video and electron microscopy to examine aggregation in models of Huntington’s disease (HD), a neurogenerative condition associated with a single gene product, the protein Huntingtin (HTT). HTT contains a polyglutamine repeat of up to ~37Q in normal individuals, and longer repeats, up to 100 or more, in HD patients. The longer the repeat, earlier the onset of disease and the more aggregation prone the protein. Aggregation may originate with liquid phase separation, leading to solid aggregates whose structure ranges from amorphous to fibrous, depending on the cellular environment. The aggregates features are quite different in sections of HD mouse brain.

 

In vitro, aggregates can be disassembled by cellular disaggregases such as the Hsp70 system, working with a AAA+ unfoldase in bacteria, fungi and plants, or just with a specific combination of Hsp70 cofactors in metazoa. We have used atomic force microscopy and cryo EM to study the Hsp70 disaggregation machinery in the process of extracting subunits from amyloid fibres and during threading of a polypeptide chain through the ATPase ring.

Host Lynne Regan

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