Amyotrophic lateral sclerois (ALS) is a debilitating neurodegenerative disease that is characterized by the death of motor neurons and a progressive loss of all motor function. The motor neuron degeneration seen in ALS has also been intimately linked to glial cell dysfunction, which includes reactive gliosis, remyelination failure and alteration in glial metabolic support. Previous studies have documented that the glial precursor cells, which generate the myelinating cells of the CNS, known as NG2+ oligodendrocyte progenitor cells, exhibit greatly enhanced proliferation during the end stage of disease in the spinal cord of the SOD1(G93A) transgenic mouse model of ALS. However, the exact extent and timing of the oligodendrocyte abnormalities in ALS patients and the mouse model are unclear. In addition, the cause of the remyelination failure, and whether this is even important for disease pathology, remains unknown. On page 571 in this issue of Nature Neuroscience, Kang et al. show that NG2+ progenitor proliferation is enhanced before disease onset in this ALS mouse model.

NG2+ oligodendrocyte progenitor cells are peppered throughout the gray matter of the spinal cord and are found in close proximity to neurons (as shown in this picture that depicts immunostaining of NG2 protein (green) and NeuN (red) in the ventral horn of mouse spinal cord). Kang et al. use genetic cell fate tracing techniques to show an enhanced proliferation of NG2+ cells in the spinal cord gray matter of young, asymptomatic SOD1(G93A) mice. Surprisingly, however, these NG2+ cells fail to mature properly or sufficiently remyelinate spinal cord motor neurons. Although the NG2+ cells are able to differentiate into oligodendrocytes, the newly formed oligodendrocytes show morphological abnormalities, such as irregularly shaped cell processes and soma, and do not fully mature, as assessed by the reduction in remyelination and expression of myelin-forming proteins. The authors also find similar NG2+ and myelination defects from postmortem spinal cord and motor cortex samples taken from ALS patients. To determine whether these defects had any effect on disease onset or progression, the authors then returned to their mouse model of ALS, and genetically inactivated the ALS-linked mutant gene SOD1(G37R) specifically from NG2+ glial progenitors. This delayed disease onset in the mice and increased their survival. These results suggest that preserving oligodendrocyte function may be a potential therapeutic target for combating this deadly disease.