title: Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology.
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.
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
authors.forename: Nolan
authors.initials: N
authors.lastname: Brown
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
authors.forename: Kholoud
authors.initials: K
authors.lastname: Alkhayer
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Clements
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Singhal
authors.affiliation: Department of Chemistry and Biochemistry, Kent State University, Kent, OH, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Gregory
authors.affiliation: Proteomics Core, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Sausan
authors.initials: S
authors.lastname: Azzam
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.|Department of Chemistry and Biochemistry, Kent State University, Kent, OH, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Freeman
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McDonough
mesh_terms: D025181:ATP Synthetase Complexes / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005260:Female; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D017966:Pyramidal Cells / Q000378:metabolism*; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D055544:beta-Globins; D056466:Histone Demethylases; D025181:ATP Synthetase Complexes
keywords: Hemoglobin expression; Histone methylation; Mass spectrometry; Mitochondrial genes; Multiple sclerosis; Pyramidal neurons
references.citation: N Engl J Med. 2000 Sep 28;343(13):938-52
references.pmid: 11006371
references.citation: J Neurosci. 2015 Nov 11;35(45):15170-86
references.pmid: 26558787
references.citation: Arch Neurol. 2001 Jan;58(1):65-70
references.pmid: 11176938
references.citation: Neurology. 2004 Feb 24;62(4):624-7
references.pmid: 14981182
references.citation: Neuroimage. 2004 Apr;21(4):1825-9
references.pmid: 15050603
references.citation: Brain Res. 1991 May 10;548(1-2):334-7
references.pmid: 1651145
references.citation: Prog Neurobiol. 1992 Dec;39(6):563-607
references.pmid: 1410442
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6643-7
references.pmid: 10359765
references.citation: Curr Protein Pept Sci. 2006 Feb;7(1):17-45
references.pmid: 16472167
references.citation: Ann Neurol. 2006 Mar;59(3):478-89
references.pmid: 16392116
references.citation: Acta Neurol Scand Suppl. 2006;183:48-50
references.pmid: 16637929
references.citation: Trends Mol Med. 2006 May;12(5):192-5
references.pmid: 16574486
references.citation: Methods Cell Biol. 2007;80:3-44
references.pmid: 17445687
references.citation: Neuroimage. 2007 May 15;36(1):19-27
references.pmid: 17398118
references.citation: J Anat. 2007 Aug;211(2):212-22
references.pmid: 17593221
references.citation: J Am Soc Nephrol. 2008 Aug;19(8):1500-8
references.pmid: 18448584
references.citation: Ann Neurol. 2008 Sep;64(3):255-65
references.pmid: 18661561
references.citation: J Cereb Blood Flow Metab. 2009 Mar;29(3):585-95
references.pmid: 19116637
references.citation: J Neurol Sci. 2009 Apr 15;279(1-2):14-20
references.pmid: 19187944
references.citation: J Comp Neurol. 2009 Aug 10;515(5):538-47
references.pmid: 19479992
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15454-9
references.pmid: 19717439
references.citation: Antioxid Redox Signal. 2010 Oct 1;13(7):1087-123
references.pmid: 20170402
references.citation: Biochim Biophys Acta. 2011 May;1812(5):630-41
references.pmid: 21295140
references.citation: Nature. 2012 Nov 15;491(7424):473-7
references.pmid: 23123858
references.citation: Acta Neuropathol. 2013 Feb;125(2):231-43
references.pmid: 23073717
references.citation: Nature. 2013 Oct 24;502(7472):489-98
references.pmid: 24153302
references.citation: Redox Biol. 2013;1:405-10
references.pmid: 24191233
references.citation: Neurochem Res. 2013 Nov;38(11):2385-96
references.pmid: 24078261
references.citation: Mitochondrion. 2014 Jan;14(1):64-72
references.pmid: 24333691
references.citation: Biochem Soc Trans. 2014 Aug;42(4):945-51
references.pmid: 25109984
references.citation: Ageing Res Rev. 2014 Jul;16:45-65
references.pmid: 24910305
references.citation: Ann Neurol. 2000 Dec;48(6):893-901
references.pmid: 11117546