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Trigger for Adult Brain Disease May Be Set During Brain Development

For release: Monday, March 5, 2007

A new study suggests that spinocerebellar ataxia type 1 (SCA1) – a genetic brain disease that manifests during adulthood – begins with subtle problems in brain development that occur during infancy.

SCA1 damages a brain region involved in motor control (the cerebellum), leading to a loss of coordination (ataxia), as well as swallowing and breathing problems that are eventually fatal.  It’s caused by mutations in the ATXN1 gene.  The study, which was published in Cell,* shows that temporarily shutting off the mutated gene during a period of cerebellar development in newborn mice significantly reduces disease severity.

“This could mean there’s a very specific time window when a treatment [for SCA1] would be most effective.  But that’s way down the road,” said Harry Orr, Ph.D., the study’s senior author and Director of the Institute of Human Genetics at the University of Minnesota in Minneapolis.  Dr. Orr is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS), including an NINDS Javits Award, given to just a handful of distinguished neuroscientists each year.

Katrina Gwinn-Hardy, M.D., a program director in the NINDS Division of Extramural Research, said Dr. Orr’s findings are probably relevant to many so-called neurodegenerative diseases, in which nerve cells that at least appeared healthy in early life deteriorate later.

“It is exciting to see important links being made between development and degeneration of the nervous system, from an academic standpoint and, even more so, from the standpoint of therapeutic implications,” she said.

Besides its implications for therapy, the study also might shed light on unexplained variability in SCA1’s age of onset.  Although the average age of onset is 30, people have developed their first symptoms anywhere from age 15 to age 50.

Some, but not all, of that variability can be traced to genetic differences.  SCA1 is caused by an abnormally long stretch of DNA, called a trinucleotide repeat expansion, nestled within the ATXN1 gene.  Longer expansions tend to cause symptoms earlier in life, but not always.  There might be environmental influences at play during the cerebellum’s development that affect when symptoms first appear, Dr. Orr said.

Dr. Orr’s study involved mice genetically engineered to carry an expanded copy of the ATXN1 gene.  He and his group inserted a switch in the gene, so that it could be turned off by adding a chemical to the mice’s drinking water. 

Mice that had the mutant gene left on developed signs of SCA1, including ataxia and degeneration of Purkinje cells – large, intricately connected cells that form an essential relay station within the cerebellum.  Mice that had the gene inactivated for the first 3 months after birth showed no signs of ataxia and only slight Purkinje cell degeneration.  Turning off the gene for just the first 2 to 3 weeks after birth also had a protective effect on the mice.

Although the normal function of ATXN1 isn’t fully understood, it’s believed to regulate transcription – the turning on of other genes.  Dr. Orr’s team performed biochemical experiments that support this theory, revealing that ATXN1 has an indirect, physical interaction with a transcription factor called the retinoid-related orphan nuclear receptor alpha(RORa).  Dr. Orr believes that ATXN1 and RORa act in concert to promote the development of Purkinje cell dendrites – the elaborate branches the cells use to receive and integrate inputs from other brain cells.

*Serra HG et al.  “RORalpha-Mediated Purkinje Cell Development Determines Disease Severity in Adult SCA1 Mice.”  Cell, November 17, 2006, Vol. 127, pp. 697-708.

-By Daniel Stimson, Ph.D.

Last Modified March 5, 2007