Clearing clumps of protein in aging neural stem cells boosts their activity

March 15, 2018, Stanford University Medical Center

Young, resting neural stem cells in the brains of mice store large clumps of proteins in specialized cellular trash compartments known as lysosomes, researchers at the Stanford University School of Medicine have found.

As the cells age, they become less proficient at disposing of these aggregates, and their ability to respond readily to "make new neurons" signals wanes. Restoring the ability of the lysosomes to function normally rejuvenates the cells' ability to activate, the researchers found.

The discovery of the aggregates in young was unexpected, in part because similar aggregates are associated with the development of neurodegenerative diseases, such as Alzheimer's. It also highlights the importance of maintaining precise control over the protein production and disposal process throughout the life and activation status of neural stem cells.

"We were surprised by this finding because resting, or quiescent, neural stem cells have been thought to be a really pristine cell type just waiting for activation," said Anne Brunet, PhD, professor of genetics. "But now we've learned they have more protein aggregates than activated stem cells, and that these aggregates continue to accumulate as the cells age. If we remove these aggregates, we can improve the cells' ability to activate and make new neurons. So if one were able to restore this protein-processing function, it could be very important to bringing older, more dormant neural stem cells 'back to life.'"

A paper describing the research will be published March 15 in Science. Brunet, an associate director of Stanford's Paul F. Glenn Center for the Biology of Aging, is the senior author. Postdoctoral scholar Dena Leeman, PhD, is the lead author.

Resting versus active neural stem cells

The researchers began their studies by looking to see what difference there might be, if any, between the gene expression profiles of resting neural stem cells and those that had been activated in response to an outside signal to launch the process to make new neurons. They also compared how the cells changed as they aged.

Leeman isolated several populations of cells for study from the brains of both young and old mice, including resting neural stem cells, activated neural stem cells and the neural cell progenitors that arise from activated stem cells. She found that resting stem cells expressed many lysosome-associated genes, while activated stem cells expressed genes associated with a protein complex involved in protein destruction called a proteasome. Strict control of production and disposal allows cells to maintain the necessary protein inventory to carry out needed cellular functions.

When Leeman stained young resting and activated neural stem cells with a dye that binds to protein aggregates, she was surprised to find the resting stem cells stained more brightly, despite the fact that resting cells have a lower rate of protein production. Leeman also found that the young resting neural stem cells accumulated these protein aggregates in their large lysosomes relatively slowly compared with their activated counterparts.

"We were really struck by the differences between resting and activated stem cells in the expression of genes involved in protein quality control," said Brunet. "The fact that these young, pristine resting stem cells accumulate protein aggregates makes us wonder whether they actually serve an important function, perhaps by serving as a source of nutrients or energy upon degradation."

Old resting stem cells, Leeman found, express fewer lysosome-associated genes and begin to accumulate even higher levels of protein aggregates.

"It's almost as if these older cells lose the ability to store, or park, these aggregates," said Brunet. "We found that artificially clearing them by either activating lysosomes in older cells or subjecting them to starvation conditions to limit their protein production actually restored the ability of these older resting stem cells to activate."

The researchers plan to continue their studies to learn what types of proteins might be contributing to the aggregates, to better understand why activated appear to favor proteasomes over lysosomes and to determine how the regulation of protein aggregation becomes disrupted during aging.

'Are they good or bad?'

"We'd like to know whether the aggregated proteins are the same in the young and old cells," said Brunet. "What do they do? Are they good or bad? Are they storing factors important for activation? If so, can we help elderly resting stem cells activate more quickly by harnessing these factors? Their existence in young suggests they may be serving an important function."

Explore further: The HLF gene protects blood stem cells by maintaining them in a resting state

More information: "Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging" Science (2018). science.sciencemag.org/cgi/doi … 1126/science.aag3048

Related Stories

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Brain stimulation plus adult neural stem cells may speed stroke recovery

January 24, 2018
Electrically stimulating implanted adult stem cells may someday speed stroke recovery, according to preliminary research presented at the American Stroke Association's International Stroke Conference 2018, a world premier ...

Using donor stem cells to treat spinal cord injury

August 28, 2017
A new study in mice published in The Journal of Neuroscience details a potential therapeutic strategy that uses stem cells to promote recovery of motor activity after spinal cord injury.

Recommended for you

Law professor suggests a way to validate and integrate deep learning medical systems

December 13, 2018
University of Michigan professor W. Nicholson Price, who also has affiliations with Harvard Law School and the University of Copenhagen Faculty of Law, suggests in a Focus piece published in Science Translational Medicine, ...

Exercise-induced hormone irisin triggers bone remodeling in mice

December 13, 2018
Exercise has been touted to build bone mass, but exactly how it actually accomplishes this is a matter of debate. Now, researchers show that an exercise-induced hormone activates cells that are critical for bone remodeling ...

Faster test for Ebola shows promising results in field trials

December 13, 2018
A team of researchers with members from the U.S., Senegal and Guinea, in cooperation with Becton, Dickinson and Company (BD), has developed a faster test for the Ebola virus than those currently in use. In their paper published ...

Pain: Perception and motor impulses arise in brain independently of one another

December 13, 2018
Pain is a negative sensation that we want to get rid of as soon as possible. In order to protect our bodies, we react by withdrawing the hand from heat, for example. This action is usually understood as the consequence of ...

Drug targets for Ebola, Dengue, and Zika viruses found in lab study

December 13, 2018
No drugs are currently available to treat Ebola, Dengue, or Zika viruses, which infect millions of people every year and result in severe illness, birth defects, and even death. New research from the Gladstone Institutes ...

Researchers give new insight to muscular dystrophy patients

December 13, 2018
New research by University of Minnesota scientists has revealed the three-dimensional structure of the DUX4 protein, which is responsible for the disease, facioscapulohumeral muscular dystrophy (FSHD). Unlike the majority ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.