The Role of NG2 Glial Cells in ALS Pathogenesis
Final rept. 30 Sep 2012-29 Sep 2014
JOHNS HOPKINS UNIV BALTIMORE MD
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A growing body of evidence suggests that glial cells are critical for the support of normal neuronal function, and in particular astrocyte and oligodendroglial dysfunction may contribute to a number of neurodegenerative diseases, including ALS. One important function of glial cells is to transport nutrients from capillaries to neurons. Much of the nutritional support is in the form of glucose however our lab and others have provided strong evidence that lactate support from oligodendrocytes via monocarboxylate transporters MCTs is a major contributor to neuronal metabolism and survival in vivo. Preliminary data from our laboratory indicates that genetic knockdown or pharmacological inhibition of glial specific monocarboxylate transporter 1 MCT1 leads to loss of spinal cord motor neurons in vitro and in vivo. In addition, our lab and others recently showed in SOD1 mutant mice NG2 cells, the progenitor cells for oligodendrocytes, upregulate NG2 and show enhanced proliferation in the ventral horn gray matter where motor neurons die. In addition, NG2 cells formed large numbers of newly generated immature, non-myelinating oligodendroglia, but no astrocytes or neurons. Finally, when we specifically protected oligodendrocyte injury in the SOD1 animal model by deleting mutant SOD1 in NG2 cells, we were able to delay disease onset by 126 days- many months longer than any other genetic ablation approach to date. We hypothesize that NG2 glial cells play a significant role in ALS pathogenesis. In particular, we are testing how human NG2 glial cells derived from ALS patient iPS cells will impact human motor neurons, also derived from human iPS cells.
- Medicine and Medical Research