Protein Aggregates in Ageing
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
Protein aggregates play a fundamental role in ageing and the disruption of protein homeostasis. Many proteins implicated in these processes are intrinsically disordered in their native states and can aggregate to produce amyloid structures with a common beta sheet structure. Once formed, these beta-sheet aggregates are thought to be damaging to cells by common mechanisms that involve disruption of the cell membrane and influx of calcium. This damage also spreads from cell to cell by mechanisms that are not well understood.
We have developed new biophysical methods to study picomolar concentrations of protein aggregates without the need to attach fluorophores. This projects aims to use these methods to quantitatively study the seeding and spreading of protein aggregates in cells using model systems based on tau and alpha synuclein. The experiments will provide new detailed and quantitative information that will allow us to determine:
(i) the extent of amplification of aggregates in the recipient cells;
(ii) which size and structure of aggregates are most effective at seeding aggregation in cells;
(iii)what aggregate concentrations are required and how fast amplification occurs.
This will provide new insights into the possible mechanisms of amplification and spreading, and why these processes may become more efficient with increasing age.
We have developed new biophysical methods to study picomolar concentrations of protein aggregates without the need to attach fluorophores. This projects aims to use these methods to quantitatively study the seeding and spreading of protein aggregates in cells using model systems based on tau and alpha synuclein. The experiments will provide new detailed and quantitative information that will allow us to determine:
(i) the extent of amplification of aggregates in the recipient cells;
(ii) which size and structure of aggregates are most effective at seeding aggregation in cells;
(iii)what aggregate concentrations are required and how fast amplification occurs.
This will provide new insights into the possible mechanisms of amplification and spreading, and why these processes may become more efficient with increasing age.
Organisations
People |
ORCID iD |
| David Klenerman (Primary Supervisor) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/P504816/1 | 01/04/2017 | 30/09/2021 | |||
| 2339512 | Studentship | BB/P504816/1 | 01/04/2017 | 31/08/2021 |
| Description | 1) Characterisation of size, structure, cell toxicity, and inflammatory potential of toxic protein aggregates found in the brain tissue of Alzheimer's disease patients. With a better characterisation of the proteins found in the brains of Alzheimer's patients, we can begin to understand the mechanisms underlying this disease, which will help contribute to the identification of new therapeutic targets. 2) Preclinical testing of AstraZeneca's antibodies for Alzheimer's disease-related proteins. This has given the company more information on the effectiveness and safety of their antibodies. More specific key findings cannot be mentioned here either due to confidentiality reasons, or not yet published. |
| Exploitation Route | 1) Assays used for the characterisation of the endogenous Alzheimer's disease brain proteins can be used to assess brain tissue from a larger cohort of Alzheimer's patients. Furthermore, the processing of these samples can be utilised by other research groups to further investigate these proteins. Lastly, our characterisations will hopefully contribute to an already growing amount of research, and help identify novel therapeutic targets. 2) AstraZeneca can see what worked or didn't work with their antibodies and reassess during the development of antibodies in the future. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |