17 March 2011. Amyotrophic lateral sclerosis is a disease not only of lower motor neurons but also of the upper motor neurons (UMNs), but whether UMN degeneration in mouse models closely mirrors human pathology has been unclear. In today's Journal of Neuroscience, researchers outline a detailed characterization of the neural degeneration that occurs in the brain of one type of ALS mouse model. Hande Ozdinler of Northwestern University in Evanston, Illinois, who led the study in collaboration with her former advisor Jeffrey Macklis of the Massachusetts General Hospital in Boston, reports that accompanying lower motor neuron deficits, there is early and specific loss of upper motor neurons in these animals. The findings may give researchers a handle on degeneration of those same neurons in humans.
Superoxide dismutase-1 (SOD1), when mutated, can cause ALS in people, and mice carrying human SOD1-G93A are a common model for the disease. Scientists knew that the mice, in addition to their well-known spinal cord motor neuron loss and associated paralysis, had upper motor neuron problems (Zang and Cheema, 2002), but as Ozdinler wrote in an e-mail to ARF: “We lacked a detailed study that showed cell-type-specific vulnerability and degradation of upper motor neurons.” The identification of new markers for neural cell types allowed the researchers to analyze corticospinal motor neurons and their neighbors more carefully than in the past.
The caveat is that the mouse’s neurobiology makes it a poor model for the upstairs portion of ALS, said Andrew Eisen of the University of British Columbia in Vancouver. “Mice and rats do not have a cortical motor neuron system like humans do,” he told ARF.
In contrast, Ozdinler believes that understanding the how upper motor neurons decay in the mice will be informative and may suggest therapeutics for people with upper motor neuron symptoms, such as stiff muscles and overactive reflexes. She used retrograde labeling to tag upper motor neurons in the SOD1-G93A mice. Even at 30 days of age—before symptoms begin—the animals evinced fewer and smaller corticospinal motor neurons than did wild-type mice or those carrying non-mutant human SOD1. The defects progressed over time as the motor neurons succumbed to apoptosis, or cell death.
Examining a variety of cell-type markers, Ozdinler found that the neurodegeneration was limited to corticospinal motor neurons and other developmentally related non-motor, subcerebral neurons. Other types of neurons and interneurons were unaffected. This is a pattern similar to that seen in human ALS. Although lower and upper motor neurons are not near neighbors, or develop along the same tracks, the authors suggest that they share something in common that makes them particularly vulnerable to SOD1 mutations.—Amber Dance.
Ozdinler PH, Benn S, Yamamoto TH, Güzel M, Brown RH Jr, 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. Abstract