by HudsonAlpha Institute for Biotechnology

Richard M. Myers, PhD, and Nicholas Cochran, PhD, in the Myers Lab at
HudsonAlpha Institute for Biotechnology. Credit: HudsonAlpha Institute
for Biotechnology

Scientists at the HudsonAlpha Institute for Biotechnology, the
University of California, San Francisco (UCSF), and the University of
Alabama at Birmingham (UAB), have identified a new risk factor for
multiple neurodegenerative diseases.

“Finding evidence for a risk factor that contributes to multiple
neurodegenerative diseases is exciting,” said Richard M. Myers, Ph.D.,
HudsonAlpha president and science director. “We already know that
these diseases share some pathologies. This work shows that the
underlying causes of those pathologies may also be shared.”

In the study, which was published April 23 in the American Journal of
Human Genetics, researchers sequenced and analyzed whole genomes of
more than 1,100 people. They found that rare variation in the gene
TET2 nearly doubled the risk of developing diseases like Alzheimer
disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal
dementia (FTD).

“The project wouldn’t have been possible without extensive
collaboration between institutions,” said first author Nicholas
Cochran, Ph.D., a senior scientist in the Myers Lab. “You end up being
able to find things that you can’t find working alone.”

Jennifer Yokoyama, Ph.D., an assistant professor of neurology at UCSF,
worked with Cochran on technical details and also was the point person
for sample collection. The majority of the samples used for the
project were collected over decades at the UCSF Memory and Aging
Center and then sequenced and analyzed at HudsonAlpha.

Once the research team had the sequence results, they analyzed the
genomes of 493 people with either AD, ALS, or FTD and 671 healthy
people. Many of the patients had early-onset versions of
neurodegenerative disease, which suggests that it is more likely that
there would be a genetic component of their illness. During genome
analysis, the researchers looked at both coding and non-coding regions
of the genome for DNA sequence variants, a strategy that allowed them
to be more confident that any possible genes they pulled out were the
real deal.

“We didn’t go in with any suspicions about what we might [get], so
we’re excited that we did find a new genetic association here,”
Cochran said. TET2 is especially exciting because it encodes a protein
that catalyzes DNA demethylation. Previous work has shown that changes
in DNA methylation happen during aging, so the authors hypothesize
that mutations in the gene could lead to a faulty TET2 protein that
disrupts how the brain ages and contributes to the development of
neurodegenerative diseases.

“Sometimes we get a hit, and it’s hard to understand what it might be
doing, but TET2 already has established roles in the brain. So this
finding really made sense,” Cochran explained.

After the team identified TET2, they looked at previously generated
genetic data from more than 32,000 healthy people and people with
neurodegenerative diseases. This data confirmed that variants in TET2,
in both protein-coding and non-coding regions, were more likely to be
present in the genomes of people with AD, ALS, or FTD than in people
without these diseases. Next steps will focus on how changes in TET2
levels or function could contribute to aging and neurodegenerative
disease.

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Study suggests a protein could play key role in neurodegenerative diseases

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More information: J. Nicholas Cochran et al. Non-Coding and
Loss-of-Function Coding Variants in TET2 are Associated with Multiple
Neurodegenerative Diseases, The American Journal of Human
Genetics(2020). DOI: 10.1016/j.ajhg.2020.03.010
Journal information: American Journal of Human Genetics