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 ...

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

New device to get people with paralysis back on their feet

February 8, 2016

The brain machine interface consists of a stent-based electrode (stentrode), which is implanted within a blood vessel in the brain, and records the type of neural activity that has been shown in pre-clinical trials to move ...

Modelling how the brain makes complex decisions

February 4, 2016

Researchers have constructed the first comprehensive model of how neurons in the brain behave when faced with a complex decision-making process, and how they adapt and learn from mistakes.

The amazing axon adventure

February 5, 2016

How does the brain make connections, and how does it maintain them? Cambridge neuroscientists and mathematicians are using a variety of techniques to understand how the brain 'wires up', and what it might be able to tell ...


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.