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Pedigrees and I-FP-CIT SPECT scan images of the four families with GCH1 mutations involved in this study.

GCH1 gene and Parkinson's risk

A study published in Brain, led by researchers at UCL Institute of Neurology, has shown that genetic mutations which cause a decrease in dopamine production in the brain and lead to a form of childhood-onset Dystonia, also play a role in the development of Parkinson’s disease.
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Leonard Wolfson Experimental Neurology Centre (LWENC)

The new Leonard Wolfson Experimental Neurology Centre (LWENC) has opened for clinical studies and trials

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Audioslide presentation on Claudia Manzoni's paper examining how fibroblasts with LRRK2 mutations react to starvation conditions and the possible deficits that they have in autophagy.

LRRK2 and autophagy in fibroblasts

In this paper Claudia Manzoni studies how fibroblast cells from people with Parkinson’s disease caused by mutations in LRRK2 react to starvation. Although the changes are quite subtle, there are differences between the way that fibroblasts that contain mutant LRRK2 respond to being starved – suggesting that there may be changes in the way that these cells regulate a key process called autophagy (a term which comes from the greek meaning to eat yourself, and is one of the ways that cells get rid of waste and recycle proteins and organellles).
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Drosophila fly model - University of Sheffield

Genetic mutations linked to Parkinson's disease

Research led by consortium researchers Dr Helene Plun-Favreau (UCL Institute of Neurology) and Dr Alex Whitworth (University of Sheffield), and collaborator Dr Heike Laman (University of Cambridge), has discovered how genetic mutations linked to Parkinson’s disease might play a key role in the death of brain cells, potentially paving the way for the development of more effective drug treatments. In the new study, published in Nature Neuroscience, the team of cross-institutional researchers showed how defects in the Parkinson’s gene Fbxo7 cause problems with mitophagy. More...

Autophagy

LRRK2 and autophagy

Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease. Here, Claudia Manzoni talks about her research (funded by the Rosetrees Trust and the Michael J. Fox Foundation) into what LRRK2 might be doing within the cell: Parkinson’s disease is a brain illness that afflicts 1 in 500 people in the UK. High profile patients, such as the actor Michael J Fox, the boxer Muhammad Ali and the late Pope John Paul II, have raised public awareness of Parkinson’s and its devastating impact. More...

Global research team discovers new Alzheimer’s risk gene

15 November 2012

  • Findings suggest immune response plays a key role in development of Alzheimer’s
  • Results welcomed by Secretary of State for Health

Scientists have discovered a rare genetic mutation that increases the risk of Alzheimer’s disease, in a study with major implications for understanding the causes of the disease. Led by scientists at UCL’s Institute of Neurology, the international team studied data from more than 25,000 people to link a rare variant of the TREM2 gene – which is known to play a role in the immune system – to a higher risk of Alzheimer’s. The findings, which are published in the New England Journal of Medicine on Wednesday 14 November, have the potential to be the most influential gene discovery for Alzheimer’s in the last two decades. Funders for the study included Alzheimer’s Research UK, the UK’s leading dementia research charity, the Medical Research Council (MRC) and the Wellcome Trust.

Huge advances in technology mean it’s now possible to study genes in much more detail, picking up rare mutations of genes that could not be found through other methods. The precise causes of Alzheimer’s are still unknown, but the disease is likely to be caused by a complex mix of genetic and environmental factors. While some genes that increase the risk of Alzheimer’s have been discovered, these discoveries do not explain all of the genetic risk. The researchers set out to uncover some of the rarer genetic variants involved in Alzheimer’s, in a bid to get a clearer picture of the causes of the disease.

Alzheimer's genes we know so far


The researchers began by sequencing the genes of 1,092 people with Alzheimer’s and a control group of 1,107 healthy people. The results showed that several mutations in the TREM2 gene occurred more frequently in people who had the disease than in those without the disease. One specific mutation, known as R47H, had a particularly strong association with the disease – appearing in 2% of people with Alzheimer’s compared to 0.5% of people without the disease. The scientists then confirmed their findings in two larger independent groups, analysing data from a total of 6,675 people with Alzheimer’s and 16,242 people without the disease. Again, they found that the R47H variant was more likely to appear in people affected by Alzheimer’s than in people without the disease.

While this mutation is extremely rare, affecting just 0.3% of the population, it increases the likelihood of developing Alzheimer’s roughly three-fold – more than any of the genes that have been linked to Alzheimer’s in the last 20 years. By identifying the mutation, the research provides valuable new information about the potential causes of Alzheimer’s disease.

The TREM2 gene controls a protein that is involved in regulating the immune response to injury or disease, acting as an ‘on/off switch’ for immune cells in the brain called microglia. The R47H variant of the gene results in a partial loss of this function, with less ability to keep these cells’ activity in check – potentially causing them to become hyperactive. The researchers now want to find out more about the role of TREM2 and better understand the effects of the R47H variant.

Dr Rita Guerreiro of UCL, the study’s lead author, said:
“These findings are particularly exciting because they give us a clear signal about what could be going wrong in Alzheimer’s disease. While the genetic mutation we found is extremely rare, its effect on the immune system is a strong indicator that this system may be a key player in the disease. The more we can understand about the causes of Alzheimer’s, the better our chances of developing treatments that could stop the disease developing.”



Prof John Hardy of UCL, a co-author on the study, said:
“This is the biggest study of its kind in Alzheimer’s to date, and it’s only been possible to achieve these results because researchers across the globe joined forces to tackle this problem. Thanks to new advances in technology it’s now possible to get a much more detailed look at the genetic risk for Alzheimer’s, picking up rare variants like this one that were previously impossible to identify. Some of the more common risk genes for Alzheimer’s are also involved in our immune response, and together these findings support an emerging theory that the immune system plays an important role in the disease.”

Health Secretary Jeremy Hunt said:
"This Government is committed to making the UK a world leader in dementia, and research of this kind has a vital role to play in helping to achieve this. Building a strong evidence base will help to improve our understanding of the disease, and achieve more for people living with dementia now and in the future."

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said:
“This is a landmark finding and reveals important new clues about the genetic causes of Alzheimer’s disease. We’re pleased to have supported this pioneering study, which will have major implications for understanding how Alzheimer’s develops – an important step towards designing new treatments. For these findings to live up to their potential and make a difference to people’s lives, it’s crucial that research building on this work continues and the role of the immune system in Alzheimer’s is fully explored. We look forward to funding more high quality research in this key area.”

Guerreiro, R. et al., 2012. TREM2 Variants in Alzheimer’s Disease. New England Journal of Medicine. Available at: http://dx.doi.org/10.1056/NEJMoa1211851 [Accessed November 15, 2012].

The research was carried out by collaborators at UCL (University College London), the Mayo Clinic, Jacksonville, FL; University of Toronto, US National Institute of Aging, Washington University School of Medicine, King’s College London, University of Nottingham, Brigham Young University, Tanz Centre for Research in Neurodegenerative Diseases, Istanbul University, Utah State University, University of Coimbra, Medical University of Lodz, University of Perugia, University of Kuopio, Aristotle University of Thessaloniki, Hospital La Grave-Casselardit, University of Manchester, Université Lille Nord de France, Cardiff University, University of Cambridge and NIH.

Page last modified on 15 nov 12 09:28