Nature Medicine | Spoonful of Medicine

Two on ALS

Even though my background is in neuroscience, I rarely write about this topic. But wo papers on amyotrophic lateral sclerosis (ALS) from the latest issue of the Journal of Neuroscience struck me as interesting to talk about.

In the first one, Fiona Laird and her colleagues generated transgenic mice that express wild-type and mutant forms of the human protein dynactin p150-Glued. As mutant forms of this molecule had been linked to ALS, they decided to explore the mechanism whereby dynactin p150-Glued contributes to the pathology. They found that expression of dynactin p150-Glued carrying a mutation that had been linked to the disease in patients led to motor neuron disease in transgenic mice, something that was not seen in mice overexpressing the wild-type form of the human protein.

The paper is very nice in that it provides a very detailed account of the neuropathology the authors see in the mouse, including some intriguing evidence of autophagic cell death. The picture below, which comes from the paper, is a silver-stained section of the spinal cord from a mutant mouse, showing dark, presumably dying, motor neurons (arrowheads) that are not seen in control mice. Unfortunately, the authors didn’t get to explore the hardcore molecular mechanisms that account for the motor neuron death. But they now have a useful system to ask more mechanistic questions to understand the role of dynactin p150-Glued in cell death and investigate its actual relationship to human ALS.


The second study deals with a question that has occupied the field for some time. We know that mutations in superoxide dismutase (SOD) are linked to familial forms of ALS, but where does SOD need to be expressed to cause disease: in neurons, in glia, in muscle? Dick Jaarsma and his colleagues tried to get at this question by generating transgenic mice that expressed mutant SOD only in neurons. The figure below, from the original paper, shows spinal cord sections from mice that expressed the mutant protein only in neurons (top left and bottom right) or ubiquitously (top middle).


This is not the first time that neuron-specific expression of SOD has been tried, but it is perhaps the first time in which it is found to effectively kill the motor neurons. In other words, these findings fly in the face of other studies reporting no motor neuron death in mice with neuron-specific expression of mutant SOD and of papers specifically identifying a contribution of extraneuronal SOD to ALS. Not unexpectedly, there is at present no definitive way to reconcile these disparate observations, other than invoking technical differences in the studies or stating that the cell-autonomous effect reported by Jaarsma et al. does not negate an additional contribution from glial SOD. What we can say for sure is that we don’t yet understand the neuron/glia/muscle interplay in ALS, and that it will be quite hard to establish if the contributions of mutant SOD from each of these sources in transgenic mice are indeed relevant to the human condition.


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