PMID- 30810907
OWN - NLM
STAT- MEDLINE
DCOM- 20201005
LR  - 20210109
IS  - 1557-1904 (Electronic)
IS  - 1557-1890 (Print)
IS  - 1557-1890 (Linking)
VI  - 14
IP  - 4
DP  - 2019 Dec
TI  - CRISPR/Cas9 Editing of Glia Maturation Factor Regulates Mitochondrial Dynamics by 
      Attenuation of the NRF2/HO-1 Dependent Ferritin Activation in Glial Cells.
PG  - 537-550
LID - 10.1007/s11481-019-09833-6 [doi]
AB  - Microglial cells are brain specific professional phagocytic immune cells that 
      play a crucial role in the inflammation- mediated neurodegeneration especially in 
      Parkinson's disease (PD) and Alzheimer's disease. Glia maturation factor (GMF) is 
      a neuroinflammatory protein abundantly expressed in the brain. We have previously 
      shown that GMF expression is significantly upregulated in the substantia nigra 
      (SN) of PD brains. However, its possible role in PD progression is still not 
      fully understood. The Clustered-Regularly Interspaced Short Palindromic Repeats 
      (CRISPR)-CRISPR Associated (Cas) protein9 (CRISPR/Cas9) system is a simple, rapid 
      and often extremely efficient gene editing tool at desired loci, enabling 
      complete gene knockout or homology directed repair. In this study, we examined 
      the effect of GMF editing by using the CRISPR/Cas9 technique in BV2 microglial 
      cells (hereafter referred to as BV2-G) on oxidative stress and nuclear factor 
      erythroid 2-related factor 2 (NRF2)/Hemeoxygenase1 (HO-1)-dependent ferritin 
      activation after treatment with (1-methyl-4-phenylpyridinium) MPP(+). Knockout of 
      GMF in BV2-G cells significantly attenuated oxidative stress via reduced ROS 
      production and calcium flux. Furthermore, deficiency of GMF significantly reduced 
      nuclear translocation of NRF2, which modulates HO-1 and ferritin activation, 
      cyclooxygenase 2 (COX2) and nitric oxide synthase 2 (NOS2) expression in BV2 
      microglial cells. Lack of GMF significantly improved CD11b and CD68 positive 
      microglial cells as compared with untreated cells. Our results also suggest that 
      pharmacological and genetic intervention targeting GMF may represent a promising 
      and a novel therapeutic strategy in controlling Parkinsonism by regulating 
      microglial functions. Targeted regulation of GMF possibly mediates protein 
      aggregation in microglial homeostasis associated with PD progression through 
      regulation of iron metabolism by modulating NRF2-HO1 and ferritin expression.
FAU - Selvakumar, Govindhasamy Pushpavathi
AU  - Selvakumar GP
AD  - Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA.
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Ahmed, Mohammad Ejaz
AU  - Ahmed ME
AD  - Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA.
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Raikwar, Sudhanshu P
AU  - Raikwar SP
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Thangavel, Ramasamy
AU  - Thangavel R
AD  - Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA.
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Kempuraj, Duraisamy
AU  - Kempuraj D
AD  - Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA.
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Dubova, Iuliia
AU  - Dubova I
AD  - Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA.
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Saeed, Daniyal
AU  - Saeed D
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Zahoor, Haris
AU  - Zahoor H
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Premkumar, Keerthivaas
AU  - Premkumar K
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Zaheer, Smita
AU  - Zaheer S
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Iyer, Shankar
AU  - Iyer S
AD  - Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA.
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA.
FAU - Zaheer, Asgar
AU  - Zaheer A
AD  - Harry S. Truman Memorial Veteans Hospital, Columbia, MO, USA. 
      zaheera@health.missouri.edu.
AD  - Department of Neurology, and Center for Translational Neuroscience, School of 
      Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital 
      Drive, Columbia, MO, USA. zaheera@health.missouri.edu.
LA  - eng
GR  - I01 BX002477/BX/BLRD VA/United States
GR  - R01 AG048205/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190227
PL  - United States
TA  - J Neuroimmune Pharmacol
JT  - Journal of neuroimmune pharmacology : the official journal of the Society on 
      NeuroImmune Pharmacology
JID - 101256586
RN  - 0 (Glia Maturation Factor)
RN  - 0 (Membrane Proteins)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Reactive Oxygen Species)
RN  - 9007-73-2 (Ferritins)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (Hmox1 protein, mouse)
RN  - EC 3.1.- (CRISPR-Associated Protein 9)
RN  - R865A5OY8J (1-Methyl-4-phenylpyridinium)
SB  - IM
MH  - 1-Methyl-4-phenylpyridinium/toxicity
MH  - Animals
MH  - CRISPR-Associated Protein 9/biosynthesis/genetics
MH  - CRISPR-Cas Systems/*physiology
MH  - Cell Line
MH  - Ferritins/biosynthesis/*genetics
MH  - Gene Editing/methods
MH  - Glia Maturation Factor/deficiency/*genetics
MH  - Heme Oxygenase-1/biosynthesis/*genetics
MH  - Membrane Proteins/biosynthesis/*genetics
MH  - Mice
MH  - Mitochondrial Dynamics/*physiology
MH  - NF-E2-Related Factor 2/biosynthesis/*genetics
MH  - Neuroglia/drug effects/*physiology
MH  - Reactive Oxygen Species/metabolism
PMC - PMC6711834
MID - NIHMS1018267
OTO - NOTNLM
OT  - CRISPR/Cas9
OT  - Glia maturation factor
OT  - Microglial cells
OT  - Parkinson's disease
COIS- Conflict of Interest The authors declare that there are no conflicts of interest.
EDAT- 2019/02/28 06:00
MHDA- 2020/10/06 06:00
PMCR- 2020/12/01
CRDT- 2019/02/28 06:00
PHST- 2018/11/16 00:00 [received]
PHST- 2019/01/08 00:00 [accepted]
PHST- 2019/02/28 06:00 [pubmed]
PHST- 2020/10/06 06:00 [medline]
PHST- 2019/02/28 06:00 [entrez]
PHST- 2020/12/01 00:00 [pmc-release]
AID - 10.1007/s11481-019-09833-6 [pii]
AID - 10.1007/s11481-019-09833-6 [doi]
PST - ppublish
SO  - J Neuroimmune Pharmacol. 2019 Dec;14(4):537-550. doi: 10.1007/s11481-019-09833-6. 
      Epub 2019 Feb 27.