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.

Brain globins in physiology and pathology

“…Exposure of neurons to hemin also upregulates Hb α-and β-chain mRNA levels. Brown et al (2016) observed enrichment of Hb in pyramidal neurons in internal layers of the multiple sclerosis (MS) cortex. They also discovered the interaction of neuronal Hb with subunits of ATP synthase, histones, and a histone lysine demethylase, suggesting that Hb 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 (Brown et al, 2016).…”

“…Brown et al (2016) observed enrichment of Hb in pyramidal neurons in internal layers of the multiple sclerosis (MS) cortex. They also discovered the interaction of neuronal Hb with subunits of ATP synthase, histones, and a histone lysine demethylase, suggesting that Hb 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 (Brown et al, 2016). Wu et al (2004) found that in AD brains, Hb binds to Aβ and co-localizes in amyloid plaques and cerebral amyloid angiopathy, promoting Aβ oligomer formation.…”

Proteomic analysis of age-related changes in ovine cerebrospinal fluid

“…The HGB expression in vertebrates was previously thought to be restricted to red blood cells, however the expression of HGB was found in both rat and human neurons [35,36] and HGB was detected in the CSF of normal human controls [37]. HGB was involved in neuronal mitochondrial energetics with epigenetic changes to histones and may provide neuroprotection in multiple sclerosis by supporting neuronal metabolism [38]. Although the sequence homology of haemoglobin β in ovis aries vs. human is 83% homology, Western blots with an anti-human haemoglobin β/γ/δ (H-76) antibody showed no reaction with the ovine CSF samples.…”

Proteomic Approaches to Decipher Mechanisms Underlying Pathogenesis in Multiple Sclerosis Patients

“…Interestingly, CSF levels of this protein have been used to discriminate CIS from RRMS patients . Furthermore, LC‐MS/MS analysis of MS cortical proteins has revealed hemoglobin interaction proteins (ATP synthase, histones, and histone lysine demethylase) . We are also currently profiling proteins in LCM‐collected WMLs and comparing them to surrounding NAWM using Quadrupole/Orbitrap MS proteomics approach.…”