Exercise and neurodegeneration

A lot has been said about the positive effects of exercise on healthy brains, but things are less clear in the disease state. In the following paper, John D. Fryer and colleagues studied the effects of exercise in one specific disease, SCA1 (SpinoCerebellar Ataxia type 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 (2011). Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science (New York, N.Y.), 334 (6056), 690-3 PMID: 22053053



SCA1 is one of the polyglutamine diseases. As explained here, poly-glutamine (aka poly-Q) diseases result from an extension in the poly-glutamine region of the causal protein. In SCA1 the causal protein is Ataxin-1 (shown below, image from wikipedia). Healthy individuals have a 6 to 35 long glutamine stretch around the middle of Ataxin-1, while individuals carrying the disease have 49 to 88 glutamines. This extension causes a change in the function of Ataxin-1, which in turn results in the death of specific neurons (neurodegeneration) and finally loss of motor functions.

So, theoretically, delayed neurodegeneration should delay the onset of symptoms. (side note: The surviving neurons might also be dysfunctional, but that is a separate discussion). This is where physical exercise comes in. Exercise has been shown to increase the production of neurotrophic factors. These factors, like BDNF or EGF, increase the production of new neurons and keep the existing ones alive and improve quality of life for the patient.

Of course biology is never that simple. Poly-glutamine proteins work on multiple levels and so does exercise. It can be beneficial for one system (e.g. by expressing neuronal survival factors), while taxing another beyond its limits (e.g. by increasing production of free radicals). In one mouse model of Huntington's Disease (another poly-Q disease) exercise has been shown to worsen symptoms.

In order to solve this dilemma empirically, the researchers put a mouse model of SCA1 on a mild exercise regimen (5 times a week). No improvement in motor performance was observed, but exercised mice lived about 15% longer than the controls. They could have called it a day there and went to publish their results in a lower journal, but Fryer and colleagues wanted to understand how this happened on a molecular level. This is very crucial. After all, mice are mice and they might be surviving longer for a reason, which might not be applicable in the human body.  

The researchers found that a neurotrophic factor, EGF, was expressed at a higher level in the brainstem of mice in response to exercise. EGF in turn decreases the expression of another protein called Capicua (Cic). To bring things full circle, the researchers showed that decreasing Cic levels in disease carrying mice through genetic means increases survival just as exercise does.

The paper doesn't present any human data. So, it is hard to conclude that same results will be observed in exercising patients (especially in a brain related disease). Hopefully, further research into the subject will provide an answer soon. Recommending exercise to pre-symptomatic patients would be a quick impact of this study. Designing a drug to mimic the molecular effects of exercise (lowering Cic levels or activity) would surely take years, but would improve many more lives.