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Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology

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Abstract

Multiple sclerosis (MS) is characterized by demyelination and progressive neurological disability. Previous studies have reported defects to mitochondria in MS including decreased expression of nuclear encoded electron transport chain subunit genes and inhibition of respiratory complexes. We previously reported increased levels of the hemoglobin β subunit (Hbb) in mitochondrial fractions isolated from postmortem MS cortex compared to controls. In the present study, we performed immunohistochemistry to determine the distribution of Hbb in postmortem MS cortex and identified proteins which interact with Hbb by liquid chromatography tandem mass spectrometry (LC-MS/MS). We found that Hbb was enriched in pyramidal neurons in internal layers of the cortex and interacts with subunits of ATP synthase, histones, and a histone lysine demethylase. We also found that Hbb is present in the nucleus and that expression of Hbb in SH-SY5Y neuroblastoma cells increased trimethylation of histone H3 on lysine 4 (H3K4me3), a histone mark that regulates cellular metabolism. These data suggest that Hbb may be a part of a mechanism linking neuronal energetics with epigenetic changes to histones in the nucleus and may provide neuroprotection in MS by supporting neuronal metabolism.

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Acknowledgments

We would like to thank the Rocky Mountain MS Center which is funded by the National Multiple Sclerosis Society and the Brain and Spinal Cord Resource Center at UCLA for tissue. This research was partially funded by NIH Grant R21NS075645 (JM and EF) and from funds from the College of Arts and Sciences at Kent State University (JM).

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    Authors and Affiliations

    1. Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA

      Nolan Brown, Kholoud Alkhayer, Robert Clements, Naveen Singhal, Shuo Li, Ernest Freeman & Jennifer McDonough

    2. Department of Chemistry and Biochemistry, Kent State University, Kent, OH, USA

      Roger Gregory & Shuo Li

    3. Proteomics Core, Case Western Reserve University, Cleveland, OH, USA

      Sausan Azzam

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    1. Nolan Brown
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    2. Kholoud Alkhayer
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    Correspondence to Jennifer McDonough.

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    Nolan Brown and Kholoud Alkhayer contributed equally to this work.

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    Brown, N., Alkhayer, K., Clements, R. et al. Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology. J Mol Neurosci 59, 1–17 (2016). https://doi.org/10.1007/s12031-015-0711-6

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