Reducing harmful proteins in the fight against dementia

November 4, 2015 by Jacqueline Pumphrey, Oxford Science Blog, Oxford University

We probably all know someone who has dementia. By 2025, there will be 1 million people affected by it in the UK. Alzheimer's disease is well known as the most common cause of dementia. But what about the third most common cause of dementia, Dementia with Lewy Bodies (DLB)?

Dementia with Lewy bodies

Frederic Henry Lewy, a prominent Jewish German-born American neurologist, first described the phenomenon that came to be known as 'Lewy bodies' in 1912. These 'bodies' are clumps of a sticky protein called alpha-synuclein that build up in nerve cells in the brain, causing damage and eventually death to these cells. Typically, they affect the cells that control thinking, memory and movement. In fact, Lewy bodies are the underlying cause of several progressive diseases affecting the brain and nervous system, including not only DLB but also Parkinson's disease.

We tend to get rid of this particular alpha-synuclein protein quite slowly, using a sophisticated 'clean-up crew' of enzymes. Studies of the brains of people who have died as a result of DLB have shown that one of these sets of enzymes is abnormally increased in the cells that contain the toxic protein clumps.

On the face of it, this may not seem to be a problem, but the system of waste-disposal enzymes is a complex one. They each have different roles and work together to regulate the level of alpha-synuclein. One set of enzymes is responsible for directly attacking the protein, whereas another – the one that is abnormally increased in DLB cases – counteracts this action. This set of enzymes works to either elongate or trim off a tag on alpha-synuclein. This tag is made up of molecules of a small protein called ubiquitin, and its regulation goes awry in patients with DLB.

Targeting the abnormally increased enzyme

Associate Professor George Tofaris, together with his research group in the Nuffield Department of Clinical Neurosciences, is working on the development of targeted biological therapies in neurodegenerative disorders. George explains that when it works, this tagging system is essentially 'a kiss of death for proteins, but a kiss of life for the cell because it gets rid of unwanted or toxic proteins'.

Alzheimer's Research UK has allocated £50,000 to George and his team to investigate how the enzymes in the ubiquitin system might be targeted, in order to improve the disposal of alpha-synuclein. So how will the team go about this ambitious project over the next two years?

The first step is to work with others on screening the hundreds of possible chemical compounds that may have an effect on such enzymes in the test tube. Researchers will identify the structures of the compounds and make computational improvements in order to refine the list of compounds that will be used in the next stage of the experiment.

Moving on the second stage, George and his team will test the compounds on human . Researchers can create cortical neurons and dopamine cells – the brain cells affected by Lewy bodies – from skin cells, by using genes that regulate gene expression. This stem-cell technique is invaluable in allowing scientists to go straight from the to working directly on a real human brain cell. The team will treat these brain cells with compounds and see which one has the most success in destroying the clumps of alpha-synuclein that can be triggered in these cells.

Neurological research such as this is mirroring the work that has been going on in the field of cancer for some time: targeting specific enzymes that have been identified in the lab as having a critical role in disease.

Paving the way for a new drug

After identifying an effective compound, the next step would be to test it in animals to see how the drug might affect the whole system, and to find out whether it can get through the , a semi-permeable membrane separating the blood from the cerebrospinal fluid.

The good news is that even if this work doesn't eventually result in a drug in tablet form, scientists will at least be in possession of good tools that can be used to manipulate alpha-synuclein and better understand how it is targeted for destruction.

Explore further: Bath scientists find clues to dementia and Parkinson's

Related Stories

Bath scientists find clues to dementia and Parkinson's

November 7, 2013
A research team from our Department of Biology and Biochemistry has identified a possible target to reduce the levels of a protein called alpha-synuclein – linked to both Parkinson's disease and dementia with Lewy bodies.

Stem cell treatment lessens impairments caused by dementia with Lewy bodies

October 15, 2015
Neural stem cells transplanted into damaged brain sites in mice dramatically improved both motor and cognitive impairments associated with dementia with Lewy bodies, according to University of California, Irvine neurobiologists ...

Single protein causes Parkinson's disease and multiple system atrophy

June 10, 2015
Several neurodegenerative disorders are caused by aggregates of a single protein known as alpha-synuclein. In collaboration with CNRS and the University of Antwerp, KU Leuven neurobiologists have discovered that the shape ...

Study to investigate the role of proteins in dementia

December 3, 2014
Researchers from Plymouth University Peninsula Schools of Medicine and Dentistry have received funding from Alzheimer's charity BRACE for a pilot study to investigate the role of proteins in the development of dementia diseases ...

Scientists make advancements that may lead to new treatments for Parkinson's

October 16, 2015
More than one million people in the United States are afflicted with Parkinson's disease, a progressive disorder of the brain that affects movement and coordination. The cause is typically unknown, and presently there is ...

Immune gene prevents Parkinson's disease and dementia

October 9, 2015
An estimated seven to ten million people worldwide are living with Parkinson's disease (PD), which is an incurable and progressive disease of the nervous system affecting movement and cognitive function. More than half of ...

Recommended for you

Scientists discover why some people with brain markers of Alzheimer's have no dementia

August 16, 2018
A new study from The University of Texas Medical Branch at Galveston has uncovered why some people that have brain markers of Alzheimer's never develop the classic dementia that others do. The study is now available in the ...

Researchers identify new genes that may contribute to Alzheimer's disease

August 14, 2018
Researchers from Boston University School of Medicine, working with scientists across the nation on the Alzheimer's Disease Sequencing Project (ADSP), have discovered new genes that will further current understanding of the ...

Deaths from resident-to-resident incidents in dementia offers insights to inform policy

August 14, 2018
Analyzing the incidents between residents in dementia in long-term care homes may hold the key to reducing future fatalities among this vulnerable population, according to new research from the University of Minnesota School ...

Scientists propose a new lead for Alzheimer's research

August 14, 2018
A University of Adelaide-led team of scientists has suggested a potential link between iron in our cells and the rare gene mutations that cause Alzheimer's disease, which could provide new avenues for future research.

Eye conditions provide new lens screening for Alzheimer's disease

August 8, 2018
Alzheimer's disease is difficult to diagnose as well as treat, but researchers now have a promising new screening tool using the window to the brain: the eye.

Potential indicator for the early detection of dementias

August 7, 2018
Researchers at the University of Basel have discovered a factor that could support the early detection of neurodegenerative diseases such as Alzheimer's or Parkinson's. This cytokine is induced by cellular stress reactions ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.