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Phe28B10 Induces Channel-Forming Cytotoxic Amyloid Fibrillation in Human Neuroglobin, the Brain-Specific Hemoglobin
journal contribution
posted on 2016-11-15, 00:00 authored by Sheetal Uppal, Amit Kumar Singh, Richa Arya, Debanjan Tewari, Neha Jaiswal, Abhijeet Kapoor, Amal Kanti Bera, Alo Nag, Suman KunduSince
its discovery, neuroglobin (Ngb), a neuron-specific oxygen
binding hemoglobin, distinct from the classical myoglobin and blood
hemoglobin, has attracted attention as an endogenous neuroprotectant.
Recent reports suggest that Ngb protects neurons from brain stroke,
ischemic stress-induced degeneration, and other brain disorders. Proteins
with a specific role in neuroprotection are often associated with
neurodegeneration, as well, depending on the cellular environment
or specific cellular triggers that tilt the balance one way or the
other. This investigation explored the potential role of Ngb in amyloid
fibril-related neuronal disorder. Ngb was capable of amyloid formation in vitro at neutral pH and ambient temperature, in both
apo and holo forms, albeit at a slower rate in the holo form, unlike
other hemoglobins that exhibit such behavior exclusively in the apo
states. Elevated temperature enhanced the rate of fibril formation
significantly. The B-helix, which is known to play a major role in
Ngb ligand binding kinetics, was found to be amyloidogenic with the
Phe28B10 amino acid side chain as the key inducer of fibrillation.
The Ngb amyloid fibril was also significantly cytotoxic to neuroblastoma
cell lines, compared to those obtained from reference hemoglobins.
The Ngb fibril probably promoted toxicity by inducing channel formation
in the cell membrane, as investigated here using synthetic lipid bilayer
membranes and the propidium iodide uptake assay. These findings imply
that Ngb plays a role in neurodegenerative disorders in vivo, for which there seems to be indirect evidence by association. Ngb
thus presents a novel prospect for understanding amyloid-related brain
disorders beyond the limited set of proteins currently investigated
for such diseases.
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channel formationbrain disordersHuman NeuroglobinNgb ligand binding kineticsapo statesholo formfibril formationRecent reportsblood hemoglobinambient temperaturePhe 28 B 10 Induces Channel-Forming Cytotoxic Amyloid FibrillationElevated temperatureNgb fibrilNgb amyloid fibrilunderstanding amyloid-related brain disordersholo formsneuron-specific oxygen binding hemoglobinneuroblastoma cell linesischemic stress-induced degenerationamyloid fibril-relatedamyloid formationbrain strokeacid side chainPhe 28 B 10cell membraneBrain-Specific Hemoglobinreference hemoglobinslipid bilayer membranespropidium iodide uptake assayrolenovel prospectneurodegenerative disorders
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