Newly identified protein may play an important role in metabolic changes associated with ALS

A new series of studies conducted by Robert Kalb, MD, of the Children’s Hospital of Philadelphia and University of Philadelphia School of Medicine, and colleagues employed in vitro and in vivo models of ALS to establish a connection between expression of mutant SOD1 or TDP-43 and changes in key regulatory mechanisms for maintaining cellular energy levels.

Studies in recent years have established that in some mouse models of ALS, as well as in a subgroup of ALS patients, there is an alteration in the balance of energy expenditure which cannot be accounted for by parameters associated with ALS symptoms. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and the authors hypothesized that it might be activated in ALS models. Their studies showed an increase of AMPK activity in mixed cell cultures derived from spinal cord, and in a mouse model,  both of which expressed mutant copper zinc superoxide dismutase 1 (mSOD1), a gene which is responsible for some familial ALS. By adding an AMPK antagonist, the researchers observed that they could prevent mSOD1-induced motor neuron in vitro.

To further investigate the role of AMPK in vivo, Kalb’s team used roundworm Caenorhabditis elegans models (C.elegans) to express human mSOD1. Locomotor activity — swimming and crawling — was significantly reduced in these transgenic worms. This functional loss was partially rescued by knockdown of AMPK activity. In further related experiments, the authors used another worm model expressing a mutant TDP-43 gene, which also underlies some familial ALS. Similar to the mSOD1 models, these worms exhibited locomotor defects which were partially reversed when AMPK activity was reduced.

Taken together, these intriguing studies suggest that AMPK, and related downstream pathways, may provide the link between the gross metabolic changes, muscle atrophy, and motor neuron degeneration in ALS. These findings may lead to a new direction in developing treatment for ALS, as well as other neurodegenerative disorders.

For more information about the study, please click here