The role of exercise in Spinocerebellar Ataxia type 1

Claire Williams, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP

Spinocerebellar ataxia type 1 (SCA1) is a genetic neurodegenerative disease that begins with impaired gait and balance followed by progressive loss of motor skills and a premature death. The underlying defect in SCA1 is an expansion of a CAG repeat encoding a polyglutamine tract in the Ataxin1 gene. In this weeks Science, a study uses a mouse model to determine the effect of exercise on the prognosis of this disease (1).

SCA1 mice between 4 and 8 weeks of age were split into a mild exercise group or a no exercise group. The exercise group showed a highly significant increase in life span compared with the no exercise group. To try and determine the cause of this difference the levels of multiple growth factors were measured in the brains of the two groups of mice. The level of epidermal growth factor (EGF) was increased in the brainstem of the mice that were included in the exercise programme. A transcriptional repressor called Capicua (Cic) lies downstream of the EGF signalling pathway and also interacts with Ataxin1. The levels of Cic were thus investigated and found to be decreased in the brainstem in response to exercise. To determine the importance of decreased Cic levels in the increased survival time of SCA1 mice, the SCA1 mice were bred with Cic knockdown mice. The resultant mice showed improved motor performance and decreased neuropathology when compared with SCA1 mice expressing normal levels of Cic. Given that Cic acts as a transcriptional repressor, microarrays were performed to look at the expression of a large number of genes in the brains of SCA1 mice. Interestingly it appears as though the mutant Ataxin1 causes Cic to bind tighter to some transcription sites (repressing their transcription) and less tightly to others (increasing their transcription). How these differing effects are mediated requires further investigation.

In conclusion, this paper suggests that exercise may have beneficial effects in slowing the progression of neurodegenerative diseases. It also raises the possibility that therapeutically decreasing the levels of Cic, or inhibiting its interaction with Ataxin1 may be of benefit to patients with SCA1.

References: 

1. Fryer JD, Yu P, Kang H, Mandel-Brehm C, Carter AN, Crespo-Barreto J, Gao Y, Flora A, Shaw C, Orr HT, Zoghbi HY. Exercise and Genetic Rescue of SCA1 via the Transcriptional Repressor Capicua. Science 2011 Nov;334(6056):690 -693.
doi: 10.1126/science.1212673

Story image from Wikimedia Commons.