La Jolla, November 9, 2011 – Al La Spada, MD, PhD, chief of the division of genetics in the UC San Diego department of pediatrics, and professor of cellular and molecular medicine, neurosciences and biological sciences, used a variety of transgenic mouse models to show that SCA7 results from genetic dysfunction in associated non-neuronal support cells to affected neurons. The findings were published in the November 9 issue of the Journal of Neuroscience.
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurological disorder in which cells in the cerebellum and brainstem degenerate, resulting in progressive loss of physical coordination and possible blindness. Its pathology is similar to other neurodegenerative diseases like Parkinson’s, Huntington’s and amyotrophic lateral sclerosis. Both the cause and a treatment, are currently unknown.
“We show that dysfunction in a variety of cell types contributes to SCA7,” shares La Spada. “If you can improve function in any of these cell types, you have a reasonable chance of improving treatment of the disease.”
In collaboration with researchers at UC San Diego School of Medicine and University of Washington, the La Spada research group created a transgenic mouse in which the key gene mutation that causes SCA7 could be easily manipulated. By creating and comparing mice that expressed the mutant gene only in targeted cells, La Spada said the scientists made two unexpected discoveries: First, when the gene mutation was eliminated from Bergmann glia, neurodegeneration continued unabated and still involved dysfunction and degeneration of the Bergmann glia themselves. Second, when the mutation was excised from Purkinje neurons and the olivary complex, there was significantly less neurological damage and Bergmann glia remained intact.
“The first result highlights the relatively new idea that degeneration goes both ways,” said La Spada. “It isn’t just neurons becoming affected when their support cells dysfunction. The Bergmann glia didn’t express the mutant gene, but they still degenerated. This shows the bilateral relationship between neurons and non-neuronal cells. They’re equal partners, in both normal functioning and in disease.
“The second result underscores the relevance of Purkinje cells and the olivary neuron circuit in the brainstem to SCA7. When it’s dysfunctional, degeneration occurs. This is crucial for our understanding of this disease, and should enable us to develop more specific therapeutic approaches. Although we have our work cut out for us, we now have a better idea of what we’re up against.”
Funding for this research came, in part, from the National Institutes of Health.
Co-authors of the study are Stephanie A. Furrer, Mathini S. Mohanachandran, Sarah M. Waldherr, Christopher Chang and Bryce L. Sopher, of the UCSD Department of Neurology; Vincent A. Damian, UCSD Department of Biochemistry; Gwenn A. Garden, UCSD Department of Neurology and Center on Human Development and Disability, University of Washington.
By Shivani Singh, M.S., Sr. Writer, Dept of Pediatrics, UC San Diego, Rady Children’s Hospital-San Diego