A Yale-led study reveals, for the first time, the process by which a particular genetic mutation causes seizures and ataxia, the neurodegenerative disorder believed to have afflicted Abraham Lincoln. The study appears online in the Early Edition of the Proceedings of the National Academy of Sciences.
Spinocerebellar Ataxia Type 5 (SCA5) is an inherited, progressive condition of the central nervous system that typically begins in midlife with loss of coordination of the hands and arms, impaired ability to walk and sometimes slurred speech. Abraham Lincoln, who had an awkward, uncoordinated gait, is believed to have suffered from SCA5.
Earlier studies had identified genetic mutations in the protein beta3 spectrin as the cause of SCA5. In this new study, investigators at Yale, Harvard and the Jackson Laboratories set out to determine how this happens by studying the cellular and molecular consequences of removing beta3 spectrin from the brains of mice.
The research provided the first detailed glimpse into the pathology associated with the loss of beta3 spectrin. Researchers found that without beta3 spectrin, certain key neurotransmitter receptors and transporters fail to assemble properly in the cerebellum and in regions of the brain that involve memory as well as cognitive and other brain functions. These receptors, they discovered, are not lost, just misplaced. As a result, mice lacking beta3 spectrin are ataxic and prone to seizures.
Senior author Jon S. Morrow, M.D., Ph.D., professor of pathology and molecular, cellular and developmental biology at Yale, says the findings were unexpected. “We were surprised by the selectivity in the loss of certain key neurotransmitter transporters and receptors in the afflicted synapses, which affected the functioning of the cerebellum,” he said. “Given the widespread distribution of spectrins in all cells and tissues, we now suspect that other neurologic diseases, as well as diseases in other organs, may arise from defects in spectrin.”
SCA5 is a genetic disease, so therapies designed to directly target the defect in beta3 spectrin in humans are probably far in the future. However, note the researchers, understanding the precise receptors and transporters affected by the loss of beta3 spectrin may point the way to key molecules in the brain that account for symptoms of the disease, and that may prove to be attractive and readily assessable targets for the development of new therapeutics.
Other authors are Michael C. Stankewich, Thomas Ardito, Lan Ji and Jung Kim of Yale University; Samuel E. Lux of the Children’s Hospital in Boston; Babette Gwynn, Raymond F. Robledo and Luanne L. Peters of the Jackson Laboratory in Bar Harbor, Maine. The study was supported by grants from the National Institutes of Health.