Reducing harmful proteins in the fight against dementia

November 4, 2015 by Jacqueline Pumphrey, Oxford Science Blog

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

Study shows video games could cut dementia risk in seniors

November 16, 2017
Could playing video games help keep the brain agile as we age?

New player in Alzheimer's disease pathogenesis identified

November 14, 2017
Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown that a protein called membralin is critical for keeping Alzheimer's disease pathology in check. The study, published in Nature Communications, ...

Biomarker may predict early Alzheimer's disease

November 10, 2017
Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a peptide that could lead to the early detection of Alzheimer's disease (AD). The discovery, published in Nature Communications, may ...

Smell test challenge suggests clinical benefit for some before development of Alzheimer's

November 10, 2017
Researchers at Columbia University Medical Center (CUMC) and the New York State Psychiatric Institute (NYSPI) may have discovered a way to use a patient's sense of smell to treat Alzheimer's disease before it ever develops. ...

How SORLA protects against Alzheimer's disease

November 7, 2017
Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new protective function for a brain protein genetically linked to Alzheimer's. The findings, published in the Journal of Experimental ...

Saving neurons may offer new approach for treating Alzheimer's disease

November 6, 2017
Treatment with a neuroprotective compound that saves brain cells from dying also prevents the development of depression-like behavior and the later onset of memory and learning problems in a rat model of Alzheimer's disease. ...


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.