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