A hormone-like factor, VAMP -associated protein (VAP) has been implicated in both amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and spinal muscular atrophy).
Recently, mutations in the human VAP have been identified in familial forms of ALS, but the role of a critical portion of that molecule called major sperm protein or MSP remained a mystery until Baylor College of Medicine and the University of Alabama at Birmingham scientists found that it plays a role in energy production in striated muscles (such as those attached to the skeleton), in part by regulating how the mitochondria (the cell’s energy source) are arrayed and function.
A report of their work appears in the current issue of the journal Developmental Cell.
Possible mechanism for ALS
The VAPs are highly conserved proteins that have been identified in organisms from yeast to human. One end of VAP is secreted and is named the major sperm protein (MSP).
"Our findings provide a possible mechanism for this disease and one that is not necessarily restricted to this gene and protein," said Dr. Hugo Bellen, professor of molecular and human genetics and director of the Program in Developmental Biology at Baylor and a senior author of the report.
"ALS is a motor neuron disease. The motor neurons problems seem to first develop defects at the synapse (where nerve cells transfer information) and they subsequently die." Bellen is also a Howard Hughes Medical Institute investigator.
Pathology of ALS
Individuals who suffer from ALS undergo death of neurons that control muscles throughout the body. Those who develop the disease lose the ability to move, talk and breathe on their own. Eventually, they die. Although a variety of cellular biological defects seem to be involved in the motor neuron death, mitochondria have been implicated in the pathology of ALS. Mitochondria are organelles within cells that are their "powerhouses."
Bellen and members of his laboratory got involved in the study when they thought that the gene associated with VAP played an important role in an activity at the synapse. They bred fruit flies (Drosophila melanogaster) to lack the protein and found no obvious defect in synaptic transmission. However, loss of the protein proved lethal.
Through a series of experiments in fruit flies by Dr. Hiroshi Tsuda in the Bellen laboratory and those carried out in the worm (C. elegans) in the lab of his colleague, Dr. Michael Miller, an associate professor of cell biology at UAB, they found that:
- Motor neurons secrete the MSP domain, which acts like a hormone.
- These secreted MSPs signal through two novel players, Robo and Lar-like receptors present on the surface of striated muscles. The receptors act to affect the localization and patterns of mitochondria, stabilizing them in the muscle.
Roles of maintenance, energy metabolism
The Robo and Lar-like receptors were previously characterized as growth cone guidance receptor pathways that are known to guide the growth of axons during developmental stages. Surprisingly, the receptors also play roles in the adult stages: mitochondria maintenance and energy metabolism.
In studies of flies and worms with mutant VAP, the muscle mitochondria are small and disorganized, and fail to fulfill their roles in energy production. However, their problems can be resolved when a normal form of the gene is expressed in their nervous systems only, said Bellen.
"This neuronal expression of VAP rescues the mitochondria in the muscles," he said. "They can fly again."
Miller found a similar activity in the worms and showed that the secreted MSP binds to growth cone guidance receptors, Robo and Lar-like in muscles that mediate mitochondrial dynamics.
Pathways mediated by MSP
Their work implicates a novel mechanism by which ALS may occur: neuronally secreted MSP is required to maintain energy metabolisms in muscles through mitochondrial placement and function. The pathways mediated by MSP and its receptors might cause or contribute to cell death observed in ALS patients.
Others who took part in this work include Sung Min Han, Youfeng Yang, Jack Vibbert, Pauline Cottee, Se-Jin Lee,and Jessica Winek of UAB, and Claire Haueter of the Howard Hughes Medical Institute.
Funding for this work came from the American Cancer Society, the Muscular Dystrophy Association, the University of Alabama at Birmingham Clinical Nutrition Center or Obesity-Related Pilot Feasibility Studies grant, the ALS Association and the Howard Hughes Medical Institute.