Using the cell’s internal machinery to break down protein plaques in dementia

Research projects: Isolation of cell-intrinsic protein aggregation handling machinery 

Lead Investigator: Dr Edward Avezov

  • Institution: University of Cambridge 
  • Grant type: PhD studentship
  • Duration: 36 months 
  • Amount: £85,000

Why did we fund this research?

Comments from our Research Network volunteers:

 I appreciate the fact that this project pursues a different research approach from other studies in the field and that results from the project could inform future early intervention strategies in the development of dementia.

Project summary

In several types of dementia, protein plaques form in and around brain cells. These protein plaques are toxic and are believed to make the cell sick, eventually causing the cell to die. However, cells have ‘quality control system’ that can break down these proteins. This project aims to understand how this quality control works in more detail and to uncover potential targets for future drug therapies. 

The background 

The shape of proteins is directly linked to how they function in cells. Proteins fold into the correct shape, which in turn means that they work correctly. This happens in all of the body’s cells, including the brain. If a protein folds in the wrong way and becomes misfolded or unfolded, cells have in built machinery to detect this. This machinery may try to repair the protein or break it down and recycle it. 

Misfolded proteins can become very “sticky” and clump together to form plaques. These plaques can be hard for a cell to break down. In some dementias, protein plaques can case brain cells to stop functioning and eventually die. For example, amyloid protein plaques are a hallmark of Alzheimer’s disease.  

What does this project involve?

The researchers are looking to find a novel way of preventing these misfolded proteins from building up in the brain by using the quality control system brain cells already have. To do this, they need to understand how that quality control system works and what ‘moving parts’ the system contains. 

To do this, the researchers have previously developed a tool to watch this process in living cells from down a microscope. This tool is an artificial protein that the cells make which has the ability to clump together to form protein plaques similar to those seen in dementia. This artificial protein is fluorescent, which allows the researchers to track its movements within cells in real time. 

By looking at how this artificial protein interacts with different parts of the cell, the researchers can learn more about how brain cells quality control the proteins they make. 

How will this project help people with dementia?

There is currently a great deal of study into how we can reduce the protein plaques in the brains of people living with dementia in the hopes of either reducing or preventing brain cell death. To try and save brain cells from dying, we need to identify new targets in cells which might help us to do this. Once we have those targets, we can design drugs which target those parts of the cell in the hope that they will reduce the build up of these protein plaques. 

This project is using cutting edge techniques to try and identify the parts of the quality control system for proteins we could target using drugs, which might give us more potential therapies for dementia for the future. 

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