AMPK amplifies Huntington's disease

July 18, 2011

A new study describes how hyperactivation of AMP-activated protein kinase (AMPK) promotes neurodegeneration in Huntington's disease (HD). The article appears online on July 18, 2011, in The Journal of Cell Biology.

The aggregation of mutant in HD disrupts many , including metabolism. —a protein that balances a cell's energy production and usage—is abnormally active in the brains of mice with HD, but whether the kinase protects neurons from the metabolic imbalances associated with HD or whether AMPK contributes to neuronal death is unknown.

Yijuang Chern and colleagues determined that the alpha1 isoform of AMPK was specifically activated and translocated into the nuclei of neurons in a mouse model of HD, whereas AMPK-alpha2 was unaffected. An inhibitor of Ca2+/calmodulin-dependent II reduced AMPK activity, suggesting that AMPK-alpha1 is activated by this kinase, probably because Ca2+ signaling is disrupted in HD neurons.

Further stimulation of AMPK by injection of the AMPK-activating drug AICAR increased neuronal death and decreased the lifespan of HD mice. AICAR also promoted the death of neuronal cell lines, an effect reversed by an AMPK inhibitor. Active, nuclear AMPK-alpha1 promoted neuronal apoptosis by reducing expression of the cell survival factor Bcl2. Bcl2 levels and cell survival were restored by CGS21680, a drug that alleviates the symptoms of HD mice.

AMPK was also hyperactivated in the brains of human HD patients, suggesting that the kinase could be a therapeutic target. Chern now wants to investigate how AMPK-alpha1 and -alpha2 isoforms are differentially regulated in neuronal tissue.

More information: Ju, T.-C., et al. 2011. J. Cell Biol. doi:10.1083/jcb.201105010

Related Stories

Recommended for you

Synthetic 3D-printed material helps bones regrow

September 28, 2016

A cheap and easy to make synthetic bone material has been shown to stimulate new bone growth when implanted in the spines of rats and a monkey's skull, researchers said Wednesday.

Epigenetic clock predicts life expectancy

September 28, 2016

UCLA geneticist Steve Horvath led a team of 65 scientists in seven countries to record age-related changes to human DNA, calculate biological age and estimate a person's lifespan. A higher biological age—regardless of chronological ...

Engineered blood vessels grow in lambs

September 27, 2016

In a hopeful development for children born with congenital heart defects, scientists said Tuesday they had built artificial blood vessels which grew unaided when implanted into lambs, right into adulthood.

Fighting the aging process at a cellular level

September 22, 2016

It was about 400 BC when Hippocrates astutely observed that gluttony and early death seemed to go hand in hand. Too much food appeared to 'extinguish' life in much the same way as putting too much wood on a fire smothers ...

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.