Understanding how small groups of proteins are toxic to brain cells

Research project: A central role for dityrosine cross-linking in Alzheimer's and other neurodegenerative diseases'

Lead Investigator: Professor Louise Serpell
Institution: University of Sussex
Grant type: Project Grant
Duration: 36 months
Amount: £357,330

Why did we fund this project?

Comments from members of our Research Network:

"Deserves high priority as a key area for continuing investigation"

"Another piece of research looking at early diagnosis of types of dementia before symptoms show and as such important to drug/cure development"

"The aim of the objectives of the research is to find a way to diagnose AD early and I do believe that this is critical in order to allow therapies a chance to actually work before the brain becomes irreparably damaged."

What do we already know?

Toxic buildups of proteins are a key hallmark of most forms of dementia, including Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia. These buildups are formed when the proteins misfold and form large clumps that are thought to be toxic to brain cells. However, how and why these misfolded clumps appear in the brain is unknown.

Proteins are made up of building blocks called amino acids. Amino acids have various properties that can affect the shape of the protein or influence its function. One amino acid called tyrosine is able to form links to other tyrosines. These links can bond two proteins together. One thing that helps tyrosine to form these links is a process known as oxidative stress, which is known to damage cells via the release of harmful molecules called free radicals. 

Some researchers believe that it is smaller clumps of protein called oligomers that are toxic to brain cells, rather than large clumps. This is particularly the case with the Alzheimer's hallmark amyloid protein. Professor Serpell and her team believe that these oligomers could be formed by tyrosine links under conditions of oxidative stress.

What does this project involve?

The team aims to test their theory that oxidative stress leads to the formation of protein oligomers via the linking together of tyrosines. Their focus will be on the Alzheimer's hallmark amyloid and tau proteins along with alpha-synuclein, which forms Lewy bodies.

They will use tissue from human brains and samples of cerebrospinal fluid to understand whether oligomers can be detected in these samples and to understand their role. They will also understand how oxidative stress affects these proteins using experiments using the proteins in the lab. 

How will this benefit people with dementia?

It is increasingly believed that identifying dementia in the earliest stages is the key to finding an effective treatment for the condition. If oligomers are shown to be what is causing damage to brain cells and if they can be detected early on in the disease process, then this could help to diagnose the condition earlier.

Understanding more about the role of oligomers, tyrosine links and oxidative stress will also give the researchers more information that could be used in the development of future targets for treatment.  

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