One well-characterized cause of amyotrophic lateral sclerosis (ALS) is mutation of the copper-zinc isoform of superoxide dismutase (SOD), which can lead to progressive degeneration of motor neurons that results in the debilitating symptoms of the disease (see ARF related news story). But must these mutations occur in neurons to be detrimental In today’s Science, Don Cleveland of the University of California at San Diego, together with colleagues in Canada and elsewhere in the U.S., suggest not.
Using chimeric mice that develop a mixture of neuronal and non-neuronal cells expressing normal or mutant SOD, they show that it is the cellular environment that profoundly influences disease pathogenesis.
First author A. M. Clement and coworkers mixed mouse embryonic stem cells carrying normal SOD, and constitutively expressing yellow fluorescent protein (YFP), with mouse blastocysts that carry various ALS-causing SOD mutations. As their offspring aged, the authors noticed that the symptoms set in later in chimeric mice, and they lived longer. In fact, Clement et al. found a linear relationship between the percentage of wild-type cells in the chimeras and these two parameters, with 80 percent wild-type cells extending onset and lifespan by about four and three months, respectively.
To test if normal neurons were compensating for mutant ones, Clement characterized chimeras that had no normal neurons. While these animals still had profound neurodegeneration, the authors found a striking left/right difference in the numbers of surviving neurons. This correlated with the left/right asymmetric distribution of normal non-neuronal cells. For example, in one chimera, the number of ventral horn motor neurons in the left spinal cord, which had 25 percent wild-type cells, was double that of the right side, in which only two percent of the cells were normal. These results were statistically significant and indicate that normal wild-type cells can protect mutant neurons. More generally, it suggests that the cellular milieu has a profound influence on disease progression.
Flipping the coin, the authors asked if mutant non-neuronal cells could damage wild-type neurons. They found that even though some chimeras had no mutant neurons, these neurons nevertheless accumulated aggregates of ubiquitinated proteins, a hallmark of ALS. Furthermore, the extent of this aggregation was often more pronounced than in neurons expressing mutant SOD. The latter finding indicated that the part played by non-neuronal cells in pathogenesis may be as important as that played by neurons themselves.
This study raises interesting questions, not only for ALS, but for other neurodegenerative diseases that may have similar etiologies, such as Parkinson’s disease. The obvious question for now is how the damaging effects of a mutation are passed from cell to cell.
Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH, Julien J-P, Goldstein LSB, Cleveland DW. Wild-type nonneural cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 2003 October 3;302:113-117. Abstract
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