Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Abstract

Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2+ cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2+ cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.

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Figure 1: Enhanced proliferation of NG2+ cells in the spinal cord of presymptomatic ALS mice.
Figure 2: Enhanced oligodendrogenesis in the spinal cord gray matter of adult ALS mice.
Figure 3: Progressive degeneration of oligodendrocytes in the spinal cord ventral gray matter of ALS mice.
Figure 4: Apoptosis of oligodendrocytes in the spinal cord of ALS mice.
Figure 5: Early disruption of oligodendrocyte structure in the spinal cord of ALS mice.
Figure 6: Myelin abnormalities and impaired maturation of adult-born oligodendrocytes in the spinal cord of ALS mice.
Figure 7: Demyelination in gray matter regions of the motor cortex and spinal cord in human ALS.
Figure 8: Excision of mutant SOD1 (G37R) from NG2+ cells delays disease onset and prolongs survival in ALS mice.

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Acknowledgements

We thank N. Ye, I. Srivastava, S. Singh and T. Le for their excellent technical support, M. Pucak for help with Imaris software operation and quantitative analysis, J. Carmen for her contributions to the Cre/lox animal study, and H. Zhang at the Johns Hopkins University School of Public Health FACS core for assistance with NG2+ cell isolation. We thank B. Trapp (Cleveland Clinic Lerner Research Institute) for advice regarding human NG2+ cell staining, R. Dutta (Cleveland Clinic Lerner Research Institute) for advice regarding protein extraction from human tissues and B. Popko (University of Chicago) for providing Plp1-creER mice. Human samples were provided by R. Bowser (Barrow Neurological Institute), K. Trevor (SACTL-VA Biorepository Trust), T. Hyde (Lieber Institute for Brain Development and the Johns Hopkins School of Medicine), J. Glass (Emory Alzheimer's Disease Research Center, 5P50AG025688-07), and the Johns Hopkins School of Medicine Department of Neuropathology. We thank E. Mosmiller for helping with patient demographic information. We also thank A. Agarwal and A. Langseth for critical discussions. This work was supported by grants from P2ALS (D.E.B. and J.D.R.), the US National Institutes of Health (NS27036 to D.W.C., NS33958 to J.D.R. and NS051509 to D.E.B.), the ALS Association (4ZMUDE to Y.L.), the Robert Packard Center for ALS Research at Johns Hopkins, and the Brain Science Institute.

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S.H.K., Y.L., J.D.R. and D.E.B. designed the experiments. S.H.K. carried out the experiments involving NG2+ cell proliferation, cell fate analysis of NG2+ cells and oligodendrocytes, and immunohistochemical analysis of oligodendrocyte structure (Figs. 1,2,3,4,5,6 and Supplementary Figs. 1–3 and 5). Y.L. performed western blot analysis from SOD1 (G93A) mice (Supplementary Fig. 7) and ALS patients (Supplementary Fig. 8), histological analysis of human tissue (Fig. 7), analysis of ricin-injected mice (Supplementary Fig. 4), and analysis of the SOD1 (G37R)–deleted mice (Fig. 8 and Supplementary Fig. 9). M.F. performed the electron microscopic and immunogold analysis (Fig. 6 and Supplementary Fig. 6). I.L. assisted with the ricin injections. D.W.C. provided the loxSOD1 (G37R) mice. L.W.O. provided assistance with analysis of the human ALS samples. S.H.K., Y.L., J.D.R. and D.E.B. wrote the manuscript.

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Correspondence to Jeffrey D Rothstein or Dwight E Bergles.

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The authors declare no competing financial interests.

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Kang, S., Li, Y., Fukaya, M. et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16, 571–579 (2013). https://doi.org/10.1038/nn.3357

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