Aging brains need 'chaperone' proteins

January 30, 2014
Aging brains need 'chaperone' proteins
Chaperones don't just scold teenagers, they also ward off neurodegenerative disease. An age-related decline in chaperone activity underlies an increased vulnerability to molecular troublemakers.

(Medical Xpress)—The word "chaperone" refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.

Researchers at Emory University School of Medicine have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.

The researchers were studying a model of , but the findings have implications for understanding other diseases, such as Alzheimer's, Parkinson's and Huntington's. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.

The results were published this week in the journal Neuron.

Scientists led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhD devised a system in which production of a misfolding-prone protein that causes a form of spinocerebellar ataxia can be triggered artificially in mice at various ages. Both Li's are professors of human genetics at Emory University School of Medicine. The first author of the paper is BCDB graduate student Su Yang.

Spinocerebellar ataxia is an inherited neurodegenerative disease in which patients develop gait problems and a loss of coordination in mid-life, because of atrophy of the cerebellum. There are several types, each caused by a mutation in a different gene.

Most of the mutations that cause spinocerebellar ataxia involve an expansion of a "polyglutamine repeat" in a protein. Having the same protein building block (the amino acid glutamine) repeated dozens of times alters the protein's function and makes it more likely to misfold and clump together. The misfolded proteins are toxic and interfere with the normal forms of the same protein.

Huntington's disease is caused by a similar polyglutamine repeat. Misfolded proteins also play roles in Alzheimer's and Parkinson's, although their production is not driven by an inherited polyglutamine repeat in those diseases.

Li's team was trying to distinguish between two possibilities. One was that the duration of accumulation is important for disease severity; aging might allow more misfolded proteins to accumulate and become toxic over time.

Instead, the scientists observed that older animals develop disease more quickly after mutant protein production is triggered. The mutant protein accumulates more quickly in 9- and 14-month old mice than in 3-month old mice, suggesting that aged neurons are more vulnerable to the effects of the misfolded protein.

Chaperones are proteins whose job is to "prevent improper liaisons" between other proteins; they prevent the sticky regions of proteins from grabbing something they're not supposed to. Li's team identified a particular chaperone called Hsc70 whose activity declines with age in the brain, while others' activity does not.

To confirm Hsc70's importance, the researchers showed that boosting cells' levels of Hsc70 can bolster their ability to cope with misfolded proteins. Injecting mice in the cerebellum with a virus that forces cells to make more Hsc70 can slow degeneration. The researchers found that the mutant interferes with production of a called MANF (mesenchephalic astrocyte-derived neurotrophic factor) in the cerebellum and that Hsc70 can prevent this interference. Injection of a virus that forces cells to make more MANF can also slow degeneration.

Potentially, small molecules that increase Hsc70 or MANF levels could be used for treating spinocerebellar ataxia, says Xiao-Jiang Li.

Explore further: New findings on protein misfolding

More information: S. Yang, S. Huang, M.A. Gaertig, X.J. Li and S. Li Age-dependent decrease in chaperone activity impairs MANF expression leading to Purkinje cell degeneration in inducible SCA17 mice. Neuron (2013).

Related Stories

New findings on protein misfolding

September 18, 2012
Misfolded proteins can cause various neurodegenerative diseases such as spinocerebellar ataxias (SCAs) or Huntington's disease, which are characterized by a progressive loss of neurons in the brain. Researchers of the Max ...

Researchers develop new drug approach that could lead to cures for wide range of diseases

December 9, 2013
A team led by a longtime Oregon Health & Science University researcher has demonstrated in mice what could be a revolutionary new technique to cure a wide range of human diseases—from cystic fibrosis to cataracts to Alzheimer's ...

Fighting Alzheimer's disease with protein origami

July 12, 2013
Alzheimer's disease is a progressive degenerative brain disease most commonly characterized by memory deficits. Loss of memory function, in particular, is known to be caused by neuronal damage arising from the misfolding ...

Recommended for you

Cognitive cross-training enhances learning, study finds

July 25, 2017
Just as athletes cross-train to improve physical skills, those wanting to enhance cognitive skills can benefit from multiple ways of exercising the brain, according to a comprehensive new study from University of Illinois ...

Brain disease seen in most football players in large report

July 25, 2017
Research on 202 former football players found evidence of a brain disease linked to repeated head blows in nearly all of them, from athletes in the National Football League, college and even high school.

Lutein may counter cognitive aging, study finds

July 25, 2017
Spinach and kale are favorites of those looking to stay physically fit, but they also could keep consumers cognitively fit, according to a new study from University of Illinois researchers.

Zebrafish study reveals clues to healing spinal cord injuries

July 25, 2017
Fresh insights into how zebrafish repair their nerve connections could hold clues to new therapies for people with spinal cord injuries.

Brain stimulation may improve cognitive performance in people with schizophrenia

July 24, 2017
Brain stimulation could be used to treat cognitive deficits frequently associated with schizophrenia, according to a new study from King's College London.

New map may lead to drug development for complex brain disorders, researcher says

July 24, 2017
Just as parents are not the root of all their children's problems, a single gene mutation can't be blamed for complex brain disorders like autism, according to a Keck School of Medicine of USC neuroscientist.


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.