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Many Cases of Dementia May Arise From Non-Inherited DNA ‘Spelling Mistakes’

Summary: Researchers report spontaneous errors in DNA that arise as our cells divide and reproduce may be at the root of Alzheimer’s disease. The findings suggest the cause of certain neurodegenerative diseases could be traced back to embryonic development.

Source: University of Cambridge.

Only a small proportion of cases of dementia are thought to be inherited – the cause of the vast majority is unknown. Now, in a study published today in the journal Nature Communications, a team of scientists led by researchers at the University of Cambridge believe they may have found an explanation: spontaneous errors in our DNA that arise as cells divide and reproduce.s.

The findings suggest that for many people with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, the roots of their condition will trace back to their time as an embryo developing in the womb.

In common neurodegenerative diseases, toxic proteins build up in the brain, destroying brain cells and damaging brain regions, leading to symptoms including personality changes, memory loss and loss of control. Only around one in twenty patients has a family history, where genetic variants inherited from one or both parents contributes to disease risk. The cause of the majority of cases – which are thought to affect as many as one in ten people in the developed world – has remained a mystery.

A team of researchers led by Professor Patrick Chinnery from the Medical Research Council (MRC) Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the University of Cambridge hypothesised that clusters of brain cells containing spontaneous genetic errors could lead to the production of misfolded proteins with the potential to spread throughout the brain, eventually leading to neurodegenerative disease.

“As the global population ages, we’re seeing increasing numbers of people affected by diseases such as Alzheimer’s, yet we still don’t understand enough about the majority of these cases,” says Professor Chinnery. “Why do some people get these diseases while others don’t? We know genetics plays a part, but why do people with no family history develop the disease?”

To test their hypothesis, the researchers examined 173 tissue samples from the Newcastle Brain Tissue Resource, part of the MRC’s UK Brain Banks Network. The samples came from 54 individual brains: 14 healthy individuals, 20 patients with Alzheimer’s and 20 patients with Lewy body dementia, a common type of dementia estimated to affect more than 100,000 people in the UK.

The team used a new technique that allowed them to sequence 102 genes in the brain cells over 5,000 times. These included genes known to cause or predispose to common neurodegenerative diseases. They found ‘somatic mutations’ (spontaneous, rather than inherited, errors in DNA) in 27 out of the 54 brains, including both healthy and diseased brains.

Together, these findings suggest that the mutations would have arisen during the developmental phase – when the brain is still growing and changing – and the embryo is growing in the womb.

Combining their results with mathematical modelling, their findings suggest that ‘islands’ of brain cells containing these potentially important mutations are likely to be common in the general population.

“These spelling errors arise in our DNA as cells divide, and could explain why so many people develop diseases such as dementia when the individual has no family history,” says Professor Chinnery. “These mutations likely form when our brain develops before birth – in other words, they are sat there waiting to cause problems when we are older.”

dna

Combining their results with mathematical modelling, their findings suggest that ‘islands’ of brain cells containing these potentially important mutations are likely to be common in the general population.NeuroscienceNews.com image is in the public domain.

“Our discovery may also explain why no two cases of Alzheimer’s or Parkinson’s are the same. Errors in the DNA in different patterns of brain cells may manifest as subtly different symptoms.”

Professor Chinnery says that further research is needed to confirm whether the mutations are more common in patients with dementia. While it is too early to say whether this research will aid diagnosis or treatment this endorses the approach of pharmaceutical companies who are trying to develop new treatments for rare genetic forms of neurodegenerative diseases.

“The question is: how relevant are these treatments going to be for the ‘common-or-garden’ variety without a family history? Our data suggests the same genetic mechanisms could be responsible in non-inherited forms of these diseases, so these patients may benefit from the treatments being developed for the rare genetic forms.”

About this neuroscience research article

Funding: The research was funded by Wellcome, the Evelyn Trust, Medical Research Council, and the National Institute for Health Research Cambridge Biomedical Research Centre.

Source: Craig Brierley – University of Cambridge
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “High prevalence of focal and multi-focal somatic genetic variants in the human brain” by Michael J. Keogh, Wei Wei, Juvid Aryaman, Lauren Walker, Jelle van den Ameele, Jon Coxhead, Ian Wilson, Matthew Bashton, Jon Beck, John West, Richard Chen, Christian Haudenschild, Gabor Bartha, Shujun Luo, Chris M. Morris, Nick S. Jones, Johannes Attems & Patrick F. Chinnery in Nature Communications. Published October 15 2018.
doi:10.1038/s41467-018-06331-w

Cite This NeuroscienceNews.com Article
University of Cambridge”Many Cases of Dementia May Arise From Non-Inherited DNA ‘Spelling Mistakes’.” NeuroscienceNews. NeuroscienceNews, 15 October 2018.
<http://neurosciencenews.com/genetic-mistake-alzheimers-10026/>.
University of Cambridge(2018, October 15). Many Cases of Dementia May Arise From Non-Inherited DNA ‘Spelling Mistakes’. NeuroscienceNews. Retrieved October 15, 2018 from http://neurosciencenews.com/genetic-mistake-alzheimers-10026/
University of Cambridge”Many Cases of Dementia May Arise From Non-Inherited DNA ‘Spelling Mistakes’.” http://neurosciencenews.com/genetic-mistake-alzheimers-10026/ (accessed October 15, 2018).

Abstract

High prevalence of focal and multi-focal somatic genetic variants in the human brain

Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.

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