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Study in Mice Links Growth Factor to Hereditary Motor Neuron Disease

For release: Wednesday, July 7, 2004

Production of a growth factor in the spinal cord drops just before the onset of symptoms in an animal model of a rare, hereditary motor neuron disease, scientists have found. The findings point to a potential new way of treating this disease, and possibly other neurodegenerative disorders as well.

Researchers led by Albert R. La Spada, M.D., Ph.D., of the University of Washington Medical Center in Seattle, studied a motor neuron disease called X-linked spinal and bulbar muscular atrophy (SBMA, also called Kennedy's disease). This disease, which is linked to a mutation in the androgen receptor gene, causes degeneration of motor neurons in adult men. Women are sometimes affected to a milder degree. Common symptoms of SBMA include muscle weakness, cramping, and atrophy; slurred speech, and problems with swallowing. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

In the study, 1 Dr. La Spada and his colleagues developed transgenic mice with the mutated gene that causes human SBMA. They found that the mice developed neuronal degeneration and symptoms just like those found in humans with SBMA. They then measured the amount of a substance called vascular epithelial growth factor (VEGF) in the spinal cords of these mice and discovered that VEGF decreased dramatically for several months before the onset of symptoms.

SBMA is one of nine disorders characterized by strings of a repeated DNA sequence (CAG) in the gene. Each CAG sequence codes for a single amino acid called glutamine, so these CAG repeats result in a long string of glutamines (also known as a polyglutamine) that interrupts the sequence of a normal protein. In the case of SBMA, the glutamine string in the middle of the androgen receptor gene interferes with a protein signal that triggers production of VEGF, the researchers found.

Increasing the amount of VEGF or introducing an extra CBP gene into neurons reduced the amount of cell death in culture. "This provides a glimmer of hope for treatment,” Dr. La Spada says. "We can envision that gene therapy might be used to deliver a therapeutic gene to spinal motor neurons, although it is too early to know for sure.”

Previous studies have shown that VEGF helps to protect motor neurons from dying and that some forms of the VEGF gene are linked to an increased risk of amyotrophic lateral sclerosis (ALS), another disorder that causes loss of motor neurons. These results, combined with those of the SBMA study, suggest that VEGF may be essential to the long-term survival of motor neurons and that a lack of VEGF may be common to a variety of motor neuron diseases. Another recent study, in the May 27, 2004, issue of Nature, 2 found that gene therapy to increase the amount of VEGF can delay onset and slow progression of symptoms in mice with the gene for one form of hereditary ALS.

Dr. La Spada and his colleagues are now trying to determine whether restoring VEGF can reverse neurodegeneration in their transgenic mouse model for SBMA. They also hope to learn how the SBMA gene defect disrupts VEGF production.

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.


1 Sopher BL, Thomas PS Jr., LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin L-W, Libby RT, Ellerby LM, La Spada AR. "Androgen Receptor YAC Transgenic Mice Recapitulate SBMA Motor Neuronopathy and Implicate VEGF164 in the Motor Neuron Degeneration.” Neuron, March 4, 2004, Vol. 41, pp. 687-699.

2 Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND. "VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model.” Nature, May 27, 2004, Vol. 429, No. 6990, pp. 413-417.

- By Natalie Frazin


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Last Modified February 18, 2014