Energy star. When ATP drops to critical levels in the brain and spinal cord, AMPK (above) fires up to help meet energy demands. Image: MRC National Institute for Medical Research, PDB.
ALS may occur, at least in part, due to the breakdown of mitochondria that supply power to the motor nerves. But according to a new study, the ramping up of energy production to compensate for these power outages may actually do more harm than good - further aggravating the disease.
The study is published today in the Journal of Neuroscience.
The Children's Hospital of Philadelphia (CHOP) team found that the level of activated AMP-associated protein kinase (AMPK), an enzyme that helps maintain energy levels in tissues including the CNS, increased by 50% with respect to the inactive enzyme in a cellular mouse model of ALS. And, by reducing the levels of activated AMPK using the inhibitor compound C, the loss of these cultured motor neurons dropped from 50% to nearly 0%.
These results suggest that a spike in AMPK activity might contribute to neurodegeneration in ALS. Therefore, by reducing these levels, researchers might be able to slow or stop the progression of the disease.
To put this theory to the test, the CHOP team genetically reduced levels of activated AMPK in a roundworm model of ALS. The researchers found that these so-called nematodes moved more easily.
The CHOP team now hopes to take a look at mouse models of ALS to determine whether levels of activated AMPK are indeed elevated and if so, whether dropping these levels delays the progression of the disease.
Looking ahead, scientists might be able to develop drugs that reduce levels of AMPK in the CNS to treat ALS. But, CHOP neurologist Robert Kalb MD, the leader of the study, cautions that there could be downsides to such a strategy such as the exacerbation of certain conditions such as hypermetabolism or type II diabetes.
"There are all sorts of potential complications,” says Kalb. “Nothing in life is simple."
Lim, M.A., Selak, M.A., Xiang, Z., Krainc, D., Neve, R.L., Kraemer, B.C., Watts, J.L. and Kalb, R.G. (2011) Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease. Journal of Neuroscience, 32(3), 1123-1141. Abstract | Full Text
Carling, D., Mayer, F.V., Sanders, M.J. and Gamblin, S.J. (2011) AMP-activated protein kinase: nature's energy sensor. Nature Chemical Biology, 7(8), 1123-1141. Abstract | Full Text
Updated 1/25/12: ALS Today talked to CHOP neurologist Robert Kalb MD about the potential of modulating AMPK as a therapy for ALS.