NEURON, June 22, 2011: Dr. Albert La Spada – Division Chief of Genetics in UC San Diego’s Department of Pediatrics and Cellular and Molecular Medicine, and Rady Children’s Hospital-San Diego, recently identified the mechanism contributing to the transcriptional dysregulation in Spinocerebellar ataxia 7, an inherited neurological disorder.
Spinocerebellar ataxia 7 is one of several types of spinocerebellar ataxia (SCA), genetic degenerative disorders characterized by atrophy in the cerebellum of the brain, progressive loss of physical coordination – and in the case of type 7 – retinal degeneration that can result in blindness. There is currently no known cure.
"Our paper highlights a number of important emerging themes in our understanding of gene regulation in the brain," said La Spada, who is also associate director of the UCSD Institute for Genomic Medicine. "With the advent of new technologies, science has learned that the vast majority of our transcripts are non-coding (non-protein producing RNA)."
Dr. La Spada is known for his 1991 discovery of the first trinucleotide repeat disease mutation, setting an entirely new field of neurogenetics into motion. Over the past 2 decades, he has studied how neurons degenerate and why the degeneration is restricted to certain cell types in different diseases. Specifically, La Spada is interested in molecular and genetic factors that affect neuron degeneration in spinocerebellar ataxia type 7, spinal & bulbar muscular atrophy, Huntington's disease and Parkinson’s disease.
The Neuron research paper demonstrates how these non-coding RNAs help finely tune transcription regulation in the brain, and perturbation of their work is linked to disease.
“If we can figure out exactly how, we should be able to gain new insights into how the brain is so precisely regulated – knowledge that may help us better understand how the brain works," says La Spada.
La Spada et al. found two regulators for the SCA gene transcription – a process that creates a template that is regulated in neurodevelopment and degeneration. However, in persons with SCA7 in particular, one of the regulators, called CTCF, is affected by an antisense non-coding RNA which they labeled SpinoCerebellarAtaxia-AntisenseNoncodingTranscript1 or SCAANT1.
A major challenge for the La Spada Lab, and biomedical research in the 21st century at large, is to figure out what noncoding RNAs do, and how they do it. Many inherited neurological disorders are known to exhibit similar gene transcription, and these findings in SCA7 could enable further understanding of similar abnormalities with non-coding RNA function in brain diseases.
Written by: Shivani Singh, M.S., Sr. Writer, Department of Pediatrics, UC San Diego, Rady Children’s Hospital-San Diego.