Below are highlights of two recent studies in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).
Major sperm protein (MSP) appears to play a role in the production of energy in skeletal muscle via its regulation of cellular "energy factories" known as mitochondria, an MDA-supported team of scientists from Baylor College of Medicine in Houston and the University of Alabama at Birmingham has reported.
MSP is a "subunit" of the human VAPB protein, which was found in 2007 to be responsible for a form of inherited ALS called ALS8.
More recent work has shown that reduced levels of VAPB may be an initial defect that underlies the development of ALS8. Decreased levels of the protein also have been shown to correlate with disease progression in SOD1 ALS mice, and have been observed in postmortem tissue taken from people with sporadic (noninherited) ALS. Taken together, VAPB protein regulation (to include MSP protein regulation) may play a key role in the ALS disease process.
In the new findings, the researchers demonstrated that MSP exerts effects on muscle cells via signaling through "Robo" and "Lar-like" receptors that are located on the surface of skeletal muscle.
The researchers stopped MSP signaling in adult nematodes (a type of roundworm). The result was development of "massive" abnormalities in the mitochondria. In these worms, the mitochondria did not properly localize in the areas of the muscle where energy is required most, and they produced 30 to 40 percent less energy than normal.
The Baylor-University of Alabama team reported its results online January 19, 2012, in Developmental Cell. MDA supported Michael Miller, associate professor of cell biology at the University of Alabama, for this work. (See Secreted VAPB/ALS8 Major Sperm Protein Domains Modulate Mitochondrial Localization and Morphology via Growth Cone Guidance Receptors. The paper is available for purchase.)
The results help solidify a role for mitochondrial dysfunction as a major contributing factor in ALS.
Blocking activation of a protein that helps cells balance energy resulted in increased mobility, improved fertility, and reduced motor neuron degeneration and death in mouse and nematode (a type of roundworm) research models of ALS, a U.S.-based research team has reported.
The protein, an enzyme called AMP-activated protein kinase (AMPK), works as a type of "sensor" that helps regulate cellular energy supply and demand.
Results from the study confirmed that abnormally high levels of AMPK protein activity were present in spinal cord cells taken from mice affected by an ALS-like disease caused by mutations in the SOD1 gene.
The research team found that AMPK-related hypermetabolism (in which energy production is less than energy expended) exists in cell culture models, two versions of the SOD1 mouse model of ALS, and a mouse model with a disease resembling ALS caused by mutations in the TDP43 gene. Mitochondrial defects also were observed in the models.
In addition, the investigators found that:
The research team, led by neurologist Robert Kalb at the Children's Hospital of Philadelphia and the University of Pennsylvania in Philadelphia, published its results Jan. 18, 2012, in the Journal of Neuroscience. (See Reduced Activity of AMP-Activated Protein Kinase Protects Against Genetic Models of Motor Neuron Disease. The complete paper is available for purchase.)
The findings add to a growing body of evidence that suggests compromised function of the cellular "energy factories" known as mitochondria, and a resulting imbalanced metabolism, is an important factor in the complex ALS disease process.
Metabolic abnormalities previously have been observed and reported in some people with ALS and also in research mouse models of the disease, and several metabolism- and nutrition-based studies in ALS are ongoing, including:
More studies are needed to determine the potential for ALS therapies based on blocking or decreasing AMPK activity, or targeting other biological pathways and components involved in energy regulation.