Scientists have discovered that spinal cord levels of a certain growth factor fall in mice just before the onset of symptoms similar to X-linked spinal and bulbar muscular atrophy (also known as SBMA or Kennedy’s disease), a form of motor neuron disease. The research results are published in the March 4 edition of the scientific journal Neuron.
Motor neurons are nerve cells that control muscles. Motor neuron disorders cause irreversible paralysis that often progresses to death. There are no effective treatments or cures for motor neuron diseases. While spinal and bulbar muscular atrophy (SBMA) is rare, its pathology is related to more common degenerative neuromuscular disorders such as Lou Gehrig’s disease (amyotrophic lateral sclerosis), which claimed the life of the famous baseball player, and Huntington’s disease.
SBMA and Huntington’s are classified as polyglutamine diseases, which are thought to occur when a mutant protein crumples, clumps together, and damages certain cellular functions. A research team led by Dr. Albert R. La Spada, University of Washington (UW) professor of laboratory medicine, neurology, and medicine in the Division of Medical Genetics, created transgenic mice with a mutation in the gene that directs the formation of androgen receptors. In mid-adulthood, the mice experienced a gradual weakness in their hind legs accompanied by degeneration of motor neurons.
Males are more severely affected by X-linked motor neuron disorders than are female carriers of the mutation, who only occasionally show milder symptoms. Normal androgen receptors bind with male hormones, such as testosterone, and then move into the cell’s nucleus to activate the controls for producing particular chemicals. The researchers found that abnormal androgen receptors interfered with a cell’s ability to produce vascular endothelial growth factor (VEGF). VEGF is important for the general health and survival of motor neurons. VEGF has been shown to rescue motor neuron cells grown in the laboratory.
La Spada said that activating the pathway for the vascular endothelial growth factor may be one of the ways that motor neuron cells protect themselves from damage. Previous studies of Lou Gehrig’s disease also suggest that VEGF plays a role in maintaining the health of motor neurons. It is possible, La Spada added, that many motor neuron disorders might share disruption of VEGF production as part of the underlying mechanism of nerve cell degeneration.
La Spada cautioned that motor neuron disease researchers can’t exclude the role of other factors or genes at this time, and noted that additional work is necessary to see if administering VEGF to affected mice would help prevent or reverse their disease.
However, if increasing the levels of VEGF in the spinal cord could be shown to help guard the nerve cells from harm, this could have therapeutic relevance in the search for treatments for patients with motor neuron disease, La Spada said.
La Spada directs the UW Center for Neurogenetics and Neurotherapeutics. Other researchers on this study were Dr. Lisa Ellerby and Dr. Michelle LaFevre-Bernt of the Buck Institute for Age Research in Novato, Calif., and Drs. Bryce Sopher, Patrick Thomas, Ida Holm, Scott Wilke, Carol Ware, Lee-Way Jin, and Randell Libby, all of the UW.
Grants from the Muscular Dystrophy Association, National Institutes of Health, Huntington’s Disease Society of America, and Hereditary Disease Foundation funded the study. La Spada also is a recipient of a Paul Beeson Faculty Scholar in Aging Research Award from the American Foundation for Aging Research.