Nav: Home

Common factor links neurodegenerative disease in young and old

April 12, 2017

Scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), identified a common mechanism in two forms of neurodegeneration that affect young adults or the elderly. The discovery advances efforts to find better treatments and cures for these diseases. Currently, there are no cures for these conditions, which are projected to cost the nation an estimated $259 billion in 2017.

The two forms of neurodegeneration are frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL). FTD is one of the most common forms of dementia in adults under 65 years. NCL is the most common neurodegenerative disease in children and young adults. This condition is associated with lipofuscin, the excessive accumulation of fats and proteins called lipopigments in vulnerable cells and tissues of the body.

The common factor in these diseases is the protein progranulin. Progranulin is involved in many biological processes, including inflammation, tumor formation, and normal development. It is widely expressed in the body, but changes in its expression mostly affect the brain. When progranulin levels are low, brain cells die more readily when exposed to toxins. Mutations that lower progranulin levels cause FTD, whereas complete loss of progranulin leads to NCL.

"Although FTD and NCL patients differ markedly in age and clinical manifestations, we wanted to know if humans who carry FTD-related genetic mutations in progranulin share features with NCL patients," said Li Gan, PhD, associate director of the Gladstone Institute of Neurological Disease.

Identifying Lipofuscin in Humans at Risk for FTD

In a new study published in Science Translational Medicine, Gan's team took a close look at lipofuscin in humans who carry mutations in the progranulin gene. Because vision loss is one of the first symptoms of NCL, and it is accompanied by lipofuscin accumulation in the retina, the researchers first evaluated lipofuscion in the retina using confocal scanning laser ophthalmoscopy. This non-invasive imaging technique is routinely performed in patients in the clinic.

"We found that people who carry progranulin mutations were nearly twice as likely to have retinal lipofuscin deposits than healthy people," shared Michael Ward, MD, PhD, a former staff scientist at Gladstone who worked closely with Gan and was the lead author of the study. "Remarkably, they had a substantially increased number and size of lipofuscin deposits, even though they didn't have any symptoms."

After this initial discovery, the scientists evaluated the frontal cortex, the region of the brain most affected in FTD. Using postmortem tissues, Gan's team found that lipofuscin deposits also accumulated in neurons from the frontal cortex of people carrying progranulin mutations.

Lipofuscin as a Diagnostic and Therapeutic Tool

To diagnose NCL, patients often undergo testing to determine the amount of lipofuscin in peripheral blood lymphocytes, a type of white blood cell. The researchers found higher levels of NCL-like lipofuscin in lympohblasts, cells that mature into lymphocytes,in patients with NCL, and also in asymptomatic patients carrying mutations in the progranulin gene. They then restored progranulin levels to normal in these cells, which reduced the levels of NCL-like lipofuscin.

"Our study shows that lipofuscin in the retina and in blood cells could serve as an early marker of disease," said Gan, who is also a professor of neurology at UCSF. "Importantly, it also suggests that restoring the levels of progranulin to normal will prevent or help treat multiple neurodegenerative disorders."

Future studies will clarify if lipofuscin itself causes disease and whether progranulin directly contributes to lipofuscin accumulation and neuronal loss.
Other Gladstone researchers on the study include Robert Chen, Connor Ludwig, Maria Telpoukhovskaia, Ali Taubes, Sakura S. Minami, Meredith Reichert, and Shannon Leslie. Researchers from the UCSF, National Institutes of Health, National Taiwan University Hospital (Taiwan), Université de Nantes (France), Heinrich-Heine University Duesseldorf (Germany), Northwestern University Feinberg School of Medicine, Stanford Medical School, University of British Columbia, Vancouver (Canada), Harvard Medical School, and Veterans Affairs Medical Center, San Francisco also took part in the research.

Funding was provided by the National Institutes of Health; Bluefield Foundation, American Brain Foundation; That Man May See, Research to Prevent Blindness; National Eye Institute; Consortium for Frontotemporal Dementia Research; VA Merit Awards; Alzheimer's Disease Center; Philippe Foundation; National Multiple Sclerosis Society.

About the Gladstone Institutes

To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact--unsolved diseases of the brain, the heart, and the immune system. Affiliated with the University of California, San Francisco, Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.

Gladstone Institutes

Related Neurodegeneration Articles:

Buck researchers discover how cellular senescence leads to neurodegeneration
Although a link has been established between chronic inflammation and neurodegenerative diseases, there have been many open questions regarding how cellular senescence, a process whereby cells that stop dividing under stress spew out a mix of inflammatory proteins, affects these pathologies.
Protein associated with ovarian cancer exacerbates neurodegeneration in Alzheimer's
Houston Methodist scientists identified a protein found in ovarian cancer that may contribute to declining brain function and Alzheimer's disease, by combining computational methods and lab research.
Objective subtle cognitive difficulties predict amyloid accumulation and neurodegeneration
Researchers report that accumulating amyloid protein occurred faster among persons deemed to have 'objectively-defined subtle cognitive difficulties' (Obj-SCD) than among persons considered to be 'cognitively normal,' offering a potential new early biomarker for Alzheimer's disease.
KBRI team reduces neurodegeneration associated with dementia in animal models
Korean research team made up of Dr. Hyung-Jun Kim and Shinrye Lee of KBRI, and professor Kiyoung Kim of Soonchunhyang University, found a new molecular mechanism of suppressing neuronal toxicity associateded dementia and Lou Gehrig's disease.
Research gauges neurodegeneration tied to FXTAS by measuring motor behavior
Research published in Frontiers in Integrative Neuroscience by a team headquartered at the University of Kansas' Life Span Institute used a grip-force test to analyze sensorimotor function in people with the FMR1 premutation, with the aim of determining FXTAS risk and severity.
Single traumatic brain injury can have long-term consequences for cognition
A single incidence of traumatic brain injury (TBI) can lead to long-lasting neurodegeneration, according to a study of 32 individuals.
Associations of physical activity, β-amyloid with cognition, neurodegeneration
Researchers in this observational study looked at whether physical activity moderates the association of β-amyloid levels, a biomarker of Alzheimer's disease, with cognitive decline and neurodegeneration over time in clinically normal older adults.
Scientists identify interactions that stabilize a neurodegeneration-associated protein
A team of researchers led by Nicolas Fawzi, an associate professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown University, used a combination of techniques to determine the atomic interactions that stabilize the liquid, yet 'condensed' phase of FUS, which is found in a a 'solid' or aggregate phase in some people with severe cases of amyotrophic lateral sclerosis (ALS) and a type of dementia called frontotemporal dementia.
Alzheimer's disease protein links plaques to cell death in mice
A new protein involved in Alzheimer's disease (AD) has been identified by researchers at the RIKEN Center for Brain Science (CBS).
Research reveals role of fat storage cells in anti-obesity intervention
New research from a team at the Marshall University Joan C.
More Neurodegeneration News and Neurodegeneration Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

There's so much we've yet to explore–from outer space to the deep ocean to our own brains. This hour, Manoush goes on a journey through those uncharted places, led by TED Science Curator David Biello.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Dispatch 1: Numbers
In a recent Radiolab group huddle, with coronavirus unraveling around us, the team found themselves grappling with all the numbers connected to COVID-19. Our new found 6 foot bubbles of personal space. Three percent mortality rate (or 1, or 2, or 4). 7,000 cases (now, much much more). So in the wake of that meeting, we reflect on the onslaught of numbers - what they reveal, and what they hide.  Support Radiolab today at