Biological Sciences

Events and seminars

Monday Seminar Series - "Macromolecular machinery for reversing protein aggregation"

Professor Helen Saibil - Institute of Structural and Molecular biology, Birkbeck College

10th October 2022 at 12:00pm [Download iCalendar / .ics file]

Daniel Rutherford Building, G.27, Lecture Theatre 1

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 studied 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 aggregation of a-synuclein in Parkinsons disease also shows a great diversity of aggregate structures in the 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 and fluorescence microscopy, activity assays and cryo EM to study the human Hsp70 disaggregation machinery in the process of extracting subunits from a-synuclein amyloid fibres. Dense arrays of chaperones are recruited to fibre ends and carry out bursts of processive disassembly.

Host Lynne Regan, IQB3

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