Mouse model of neuromuscular disease identifies key player in motor neuron death

Scientists have created a new mouse model for spinal and bulbar muscular atrophy (SBMA), a disease characterized by adult-onset progressive weakness and degeneration of limb muscles, often resulting in the patient being confined to a wheel chair. SBMA causes the death of cells called motor neurons that control muscle function. The study, published in the March 4 issue of Neuron, presents a clearer picture of the pathology underlying SBMA and associated diseases and even points to a possible therapeutic strategy for this debilitating condition and for more common motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), that currently have no proven treatments.

SBMA belongs to a group of neurodegenerative disorders, called polyglutamine diseases, that includes Huntington’s disease and spinocerebellar ataxias. Polyglutamine diseases are thought to arise because of a mutant protein that is misfolded and subsequently clumps together to form toxic aggregates that destroy cell function and cause disease. In SBMA, a mutated gene directs production of androgen receptors with an abnormal number of consecutive residues of the amino acid glutamine. Dr. Albert R. La Spada and colleagues from the University of Washington Medical Center in Seattle created transgenic mice containing the human androgen receptor carrying 100 glutamine repeats. The mice developed a gradually progressive limb weakness around mid-adulthood that was accompanied by motor neuron degeneration, strikingly similar to what is seen in human SBMA patients. The researchers determined that the abnormal androgen receptor interfered with production of a molecule called vascular endothelial growth factor (VEGF) that is important for the general health and survival of motor neurons. Interestingly, VEGF could rescue SBMA-like motor neurons grown in the laboratory.

The researchers conclude that VEGF may play a pivotal role in motor neuron degeneration. “Our findings in SBMA suggest that activation of the VEGF pathway may be one way that the motor neuron protects itself from harmful insults and stresses. Studies of ALS (amyotrophic lateral sclerosis) also point to the VEGF axis as critical for motor neuron health, so it is distinctly possible that all motor neuron diseases share interruption of the VEGF axis as part of their pathogenesis,” explains Dr. La Spada. “If this is true, then it would have dramatic implications for treatment of motor neuron diseases.”

Bryce L. Sopher, Patrick S. Thomas, Jr., Michelle A. LaFevre-Bernt, Ida E. Holm, Scott A. Wilke, Carol B. Ware, Lee-Way Jin, Randell T. Libby, Lisa M. Ellerby, and Albert R. La Spada: “Androgen Receptor YAC Transgenic Mice Recapitulate SBMA Motor Neuronopathy and Implicate VEGF164 in the Motor Neuron Degeneration”

Published in Neuron, Volume 41, Number 5, 4 March 2004, pages 687-699.