Researchers find gene that protects against dementia in high-risk individuals

Dec 22, 2010

Neuroscientists had assumed that a mutation in the progranulin gene, which makes the progranulin protein and supports brain neurons, was sufficient to produce a kind of dementia known as frontotemporal lobar degeneration (FTLD). But now an international team of scientists led by researchers at Mayo Clinic's campus in Florida have found another genetic factor they say appears to protect against the disorder in progranulin mutation carriers.

In an article published in the Dec. 22, 2010, issue of Neurology, the medical journal of the American Academy of Neurology, the researchers report that people with a mutated progranulin gene who also inherited two copies of a specific variant of the TMEM106B gene are significantly less likely to develop FTLD or they have their disease onset delayed.

"This was an unexpected but very exciting finding because it suggests that if we could understand what TMEM106B is, and how it and its variants work, this could provide a new avenue for development of an agent that protects against FTLD," says the study's lead author, neuroscientist Rosa Rademakers, Ph.D.

The study was a follow-up to a genome-wide association study led by researchers from the University of Pennsylvania School of Medicine, which included 45 centers around the world and was published in March 2010 in Nature Genetics. This study used postmortem brain tissue to pinpoint variation in the TMEM106B gene as a risk factor for FTLD. What these patients all had in common was that they had lesions of misfolded TDP-43 proteins inside brain . Researchers found that TMEM106B variants also played a role in FTLD patients with a progranulin mutation who invariably have these brain lesions.

"This research was designed to confirm the findings of the earlier study and to expand it to see if TMEM106B could modulate progranulin levels," Dr. Rademakers says. To do this, the researchers looked for the TMEM106B variant in a new set of patients, including 82 FTLD patients who had progranulin mutations, 562 FTLD patients without mutations, as well as a group of 822 healthy controls.

In the group as a whole, they did not see a significant association with TMEM106B, but there was a very significant association between TMEM106B variants and the development of FTLD in individuals with progranulin mutations.

The researchers found that individuals with a progranulin mutation who also inherited two copies of the protective TMEM106B allele did not develop FTLD or developed it at a much later age than is typical, which is normally around age 60, Dr. Rademakers says. "Since progranulin mutation carriers produce 50 percent less progranulin protein, we believe TMEM106B may affect progranulin levels and therefore specifically works in people with progranulin mutations," she says.

In support of their hypothesis, they found that individuals carrying the protective TMEM106B allele have more progranulin in their blood plasma, suggesting that the TMEM106B allele works to increase progranulin protein levels.

"The protective form of TMEM106B leads to higher levels of progranulin in the blood. Whether it also increases the levels of progranulin in the has not yet been studied and will be the focus of our future research," Dr. Rademakers says.

Not only could the beneficial TMEM106B allele be the basis of a novel therapy for individuals with a progranulin mutation, it might also help others who are at risk, for she adds. "Subtle changes in progranulin levels have been linked to an increased risk for the development of FTLD, so now we have an interesting new lead to explore."

Explore further: Throwing a loop to silence gene expression

add to favorites email to friend print save as pdf

Related Stories

New insight into the cause of common dementia found

Nov 17, 2010

Researchers at the Mayo Clinic campus in Florida have found a clue as to how some people develop a form of dementia that affects the brain areas associated with personality, behavior, and language.

Blood test predicts chance of dementia

Mar 06, 2009

VIB (the Flanders Institute for Biotechnology, Belgium) researchers connected to the Born-Bunge Institute and the University of Antwerp discovered the amount of growth factor progranulin in blood is a predictor of Frontotemporal ...

New insight into dementia pathophysiology

Nov 17, 2010

New research unravels a key molecular pathway underlying a neurodegenerative disorder that causes a devastating type of dementia. The study, published by Cell Press in the November 18 issue of the journal Neuron, sheds light ...

More clues to midlife dementia that erases personality

Apr 16, 2008

New clues have been uncovered by University of California, Berkeley, and UC San Francisco researchers to a mystifying, hidden dementia that robs its victims of empathy and social skills, and leads to an early ...

Recommended for you

Throwing a loop to silence gene expression

8 hours ago

All human cells contain essentially the same DNA sequence – their genetic information. How is it possible that shapes and functions of cells in the different parts of the body are so different? While every cell's DNA contains ...

A nucleotide change could initiate fragile X syndrome

Sep 01, 2014

Researchers reveal how the alteration of a single nucleotide—the basic building block of DNA—could initiate fragile X syndrome, the most common inherited form of intellectual disability. The study appears ...

Gene clues to glaucoma risk

Aug 31, 2014

Scientists on Sunday said they had identified six genetic variants linked to glaucoma, a discovery that should help earlier diagnosis and better treatment for this often-debilitating eye disease.

User comments : 0