Molecular and cellular mechanisms of protein aggregation and toxicity in models of neurodegeneration. (360G-Wellcome-106249_Z_14_Z)

£1,199,452

The proposed research focuses on the molecular and cellular machinery for disaggregation and refolding of aggregated proteins. Protein quality control systems normally prevent the accumulation of toxic, misfolded species that cause degenerative diseases. Through genetic and biochemical changes of unclear origin, quality control becomes less effective with ageing, eventually resulting in late onset neurodegenerative conditions such as Alzheimers and Parkinsons diseases. Taking advantage of re cent advances in three-dimensional molecular and cellular electron microscopy, I wish to investigate the cellular machinery for processing amyloid and related aggregates of misfolded proteins. Misfolding of diverse proteins and peptides leads to deposition of amyloid fibrils with a common core structure, and the aggregation process results in cell death in amyloid diseases. The broad question is how misfolding and aggregation are kept under control during the healthy lifespan of cells and tissue s, and how these protein homeostasis functions eventually become ineffective in misfolding disease. The in vitro part of the proposed work focuses on how Hsp70 and its cofactors, a ubiquitous and abundant chaperone system in animal cells, extract proteins from aggregates and renature them. In particular, how do Hsp70, Hsp40 (J-proteins) and Hsp110 (a nucleotide exchange factor, NEF) together engage with aggregated, non-native proteins and how does the machinery operate in disaggregation? With the knowledge gained from in vitro structural and mechanistic studies, cell and animal models serve to address questions about the structural basis for disaggregation in vivo, as well as helping to identify common, underlying features in toxic gain of function from protein aggregation.

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Grant Details

Amount Awarded 1199452
Applicant Surname Saibil
Approval Committee Science Interview Panel
Award Date 2014-12-03T00:00:00+00:00
Financial Year 2014/15
Grant Programme: Title Investigator Award in Science
Internal ID 106249/Z/14/Z
Lead Applicant Prof Helen Saibil
Partnership Value 1199452
Planned Dates: End Date 2022-09-30T00:00:00+00:00
Planned Dates: Start Date 2015-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London