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 The team developed a way to sequence the genomes of individual
neurons, which allowed them to see what changes are normal and also
what happens in specific brain diseases.
"The work is at a very early stage,” senior study author Dr.
Christopher A. Walsh from Harvard Medical School in Boston told
Reuters Health by email. “We have only just developed a method that
we hope will give us new insight into how neurons age, and we hope
to use it to understand more about common forms of dementia and
degeneration.”
Scientists have long thought that aging and degenerative brain
diseases are associated with genetic changes in brain cells, but
until now, they haven't had the technology to test this theory.
Dr. Walsh's team found a way to look at all the genes within a
single neuron and then analyzed neurons from the cadavers of 15
neurologically normal individuals aged 4 months to 82 years. The
also looked at nine people diagnosed with Cockayne syndrome (CS) or
Xeroderma pigmentosum (XP), conditions caused by defects in DNA
damage repair that are associated with brain degeneration and
premature aging.
Just like cells throughout the rest of the body, the researchers
found that genetic mutations increased in number with increasing age
in normal neurons. But, they noted, brain regions associated with
age-related degenerative conditions like Alzheimer's disease and
age-related cognitive decline were especially affected, according to
the report in the journal Science.
Autopsy specimens from brains of patients with CS and XP also showed
increased numbers of mutations, which were more than twice as common
as those seen in brain cells from individuals of the same age
without those diseases.
The researchers found that mutations start occurring even as the
brain is still developing in an infant, and they estimate that by
the age of 1 year, normal brain cells have 600 to 900 single-letter
changes in their genes. By the time someone is in their 80s, there
are an estimated 2,400 changes.
The study team also identified three patterns of mutations in brain
cells across a lifetime. In one, which they called Signature A,
mutations increased with age regardless of brain region. In another,
which they called Signature B, mutations were increased in brain
regions associated with Alzheimer's disease but not in areas
associated with age-related cognitive decline.
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The third pattern, Signature C, showed a different class of genetic
mutations that are characteristic of oxidative damage, and were most
common in patients with CS and XP but also increased with age in
normal neurons.
The researchers summarized this accumulation of genetic mutations, a
form of cellular senescence, in a single term: genosenium (aging of
the genome).
“I found it surprising not just that the number of mutations
increases with age, which we sort of expected to see (though we did
not know how, or how fast, they would accumulate), but that some
types of mutations accumulate with age (Signature A), and other
biochemically distinct types of mutations (Signature B) are present
at birth and don't’ accumulate with age at all,” Dr. Walsh said.
“To be able to have the precision to dissect out these different
types of mutations was more than we could have hoped for,” he added.
“We also find that different people may accumulate mutations at
different rates, and we need to know what might control that.”
"I was surprised to see the quite clear correlation of somatic
mutations with age using a relatively small number of neurons,” said
Dr. Sarah E. Harris, a specialist in genetics at the University of
Edinburgh Center for Cognitive Aging and Cognitive Epidemiology in
the UK, who wasn’t involved in the study.
“As a geneticist interested in determining genetic influences on
cognitive ageing, it's fantastic to see the technique of single-cell
whole-genome sequencing being used to identify mutations in the
brain that are acquired during the life-course,” she told Reuters
Health by email.
SOURCE: http://bit.ly/2BiMbb8 Science, online December 7, 2017.
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