%0 Journal Article
%A Uppal, Sheetal
%A Kumar Singh, Amit
%A Arya, Richa
%A Tewari, Debanjan
%A Jaiswal, Neha
%A Kapoor, Abhijeet
%A Kanti Bera, Amal
%A Nag, Alo
%A Kundu, Suman
%D 2016
%T Phe28B10 Induces Channel-Forming Cytotoxic
Amyloid Fibrillation in Human Neuroglobin, the Brain-Specific Hemoglobin
%U https://acs.figshare.com/articles/journal_contribution/Phe28_sup_B10_sup_Induces_Channel-Forming_Cytotoxic_Amyloid_Fibrillation_in_Human_Neuroglobin_the_Brain-Specific_Hemoglobin/4269992
%R 10.1021/acs.biochem.6b00617.s001
%2 https://acs.figshare.com/ndownloader/files/6961499
%K channel formation
%K brain disorders
%K Human Neuroglobin
%K Ngb ligand binding kinetics
%K apo states
%K holo form
%K fibril formation
%K Recent reports
%K blood hemoglobin
%K ambient temperature
%K Phe 28 B 10 Induces Channel-Forming Cytotoxic Amyloid Fibrillation
%K Elevated temperature
%K Ngb fibril
%K Ngb amyloid fibril
%K understanding amyloid-related brain disorders
%K holo forms
%K neuron-specific oxygen binding hemoglobin
%K neuroblastoma cell lines
%K ischemic stress-induced degeneration
%K amyloid fibril-related
%K amyloid formation
%K brain stroke
%K acid side chain
%K Phe 28 B 10
%K cell membrane
%K Brain-Specific Hemoglobin
%K reference hemoglobins
%K lipid bilayer membranes
%K propidium iodide uptake assay
%K role
%K novel prospect
%K neurodegenerative disorders
%X Since
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.
%I ACS Publications