Ozdinler PH, Benn S, Yamamoto TH, Güzel M, Brown RH, Macklis JD. Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G⁹³A transgenic ALS mice. J Neurosci. 2011 Mar 16;31(11):4166-77. PubMed.
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Université Pierre et Marie Curie
This new study by the lab of Jeffrey Macklis assesses if, beside the well-established degeneration of (lower) spinal cord motor neurons in the widely used mutant SOD1/G93A mouse line, there is also a loss of (upper) corticospinal motor neurons (CSMNs), as is the case in actual human ALS. This is an important question and essential in order to judge the accuracy of this mouse ALS model.
Already in 2002, a study published in Neuroscience Letters by the lab of Surindar Cheema in Australia attempted to answer this question (Zang and Cheema, 2002). Both studies injected retrograde fluorogold labeling (at cervical levels) at different disease stages into high-expressing G93A mice (that reach endstage at 120 days) in order to mark the CSMNs and to assess their loss. The former study assessed loss at 60, 90, and 110 days of age (with negative littermates as controls), while the Macklis study did a more extensive approach starting at 30 days of age (then 60, 90, and 120 days) and comparing to wild-type overexpressing SOD1 mice. Interestingly, the Cheema study could identify significant degeneration of CSMNs at 90 days of age (30 percent loss) with first signs starting at 60 days. The current Macklis study clearly can identify already a significant 30 percent loss at 60 days of age, when G93A mice are still without apparent signs of hindlimb paralysis. Even more so, there is already clearly reduced soma diameter (25 percent) of CSMNs as early as 30 days of age (a classic pre-symptomatic stage) as this study finds. Importantly, the degeneration of CSMNs seems to be rather selective, as other cortical projecting neurons or even cortical interneurons are not affected.
As is often the case, an interesting finding raises an even larger number of interesting questions: In this same ALS line, if a similar precise study would be done with spinal cord MNs (maybe even with retrograde labeling), how would the two degenerative phases temporarily compare? Which neurons degrade first? Likewise, if mutant SOD1 toxicity could be reduced specifically in one of the two locations, how would it influence the other region? With modern cell type-specific gene expression profiling approaches (e.g., fluorescence-activated cell sorting or laser-microdissection), how do the two neuronal degenerative programs compare?
Despite the significant loss of CSMNs, the reactive gliosis is rather small—a strange finding if one compares to the early and fulminant gliosis in the spinal cord. Likewise, the early Cheema study actually showed degeneration of rubrospinal neurons in the midbrain as well (up to 40 percent at endstage), which is not detected in the current Macklis study.
As we often are biased by the obvious phenotype of ALS mice (hindlimb paralysis), we probably overlook many other less or even equally touched neuronal systems in these model mice. Despite the interest of analyzing the degeneration of CSMNs in ALS, it is mostly the loss of the spinal cord motor neurons that makes the disease so deadly; slowing motor neuron degeneration in the spinal cord remains, therefore, a very important goal. However, insights from CSMNs could well reveal additional candidate pathways for intervention in both neuronal populations.
References:
Zang DW, Cheema SS. Degeneration of corticospinal and bulbospinal systems in the superoxide dismutase 1(G93A G1H) transgenic mouse model of familial amyotrophic lateral sclerosis. Neurosci Lett. 2002 Oct 31;332(2):99-102. PubMed.
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