PMID- 30218400
OWN - NLM
STAT- MEDLINE
DCOM- 20190829
LR  - 20211204
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Print)
IS  - 0893-7648 (Linking)
VI  - 56
IP  - 6
DP  - 2019 Jun
TI  - Molecular Association of Glia Maturation Factor with the Autophagic Machinery in 
      Rat Dopaminergic Neurons: a Role for Endoplasmic Reticulum Stress and MAPK 
      Activation.
PG  - 3865-3881
LID - 10.1007/s12035-018-1340-1 [doi]
AB  - Parkinson's disease (PD) is one of the several neurodegenerative diseases where 
      accumulation of aggregated proteins like alpha-synuclein occurs. Dysfunction in 
      autophagy leading to this protein build-up and subsequent dopaminergic 
      neurodegeneration may be one of the causes of PD. The mechanisms that impair 
      autophagy remain poorly understood. 1-Methyl-4-phenylpiridium ion (MPP(+)) is a 
      neurotoxin that induces experimental PD in vitro. Our studies have shown that 
      glia maturation factor (GMF), a brain-localized inflammatory protein, induces 
      dopaminergic neurodegeneration in PD and that suppression of GMF prevents 
      MPP(+)-induced loss of dopaminergic neurons. In the present study, we demonstrate 
      a molecular action of GMF on the autophagic machinery resulting in dopaminergic 
      neuronal loss and propose GMF-mediated autophagic dysfunction as one of the 
      contributing factors in PD progression. Using dopaminergic N27 neurons, primary 
      neurons from wild type (WT), and GMF-deficient (GMF-KO) mice, we show that GMF 
      and MPP(+) enhanced expression of MAPKs increased the mammalian target of 
      rapamycin (mTOR) activation and endoplasmic reticulum stress markers such as 
      phospho-eukaryotic translation initiation factor 2 alpha kinase 3 (p-PERK) and 
      inositol-requiring enzyme 1alpha (IRE1alpha). Further, GMF and MPP(+) reduced Beclin 1, 
      focal adhesion kinase (FAK) family-interacting protein of 200 kD (FIP200), and 
      autophagy-related proteins (ATGs) 3, 5, 7, 16L, and 12. The combined results 
      demonstrate that GMF affects autophagy through autophagosome formation with 
      significantly reduced lysosomal-associated membrane protein 1/2, and the number 
      of autophagic acidic vesicles. Using primary neurons, we show that MPP(+) 
      treatment leads to differential expression and localization of p62/sequestosome 
      and in GMF-KO neurons, there was a marked increase in p62 staining implying 
      autophagy deficiency with very little co-localization of alpha-synuclein and p62 as 
      compared with WT neurons. Collectively, this study provides a bidirectional role 
      for GMF in executing dopaminergic neuronal death mediated by autophagy that is 
      relevant to PD.
FAU - Selvakumar, Govindhasamy Pushpavathi
AU  - Selvakumar GP
AD  - Harry S. Truman Memorial Veterans 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 - Iyer, Shankar S
AU  - Iyer SS
AD  - Harry S. Truman Memorial Veterans 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 Veterans 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 Veterans 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 - Thangavel, Ramasamy
AU  - Thangavel R
AD  - Harry S. Truman Memorial Veterans 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 Veterans Hospital, Columbia, MO, USA.
FAU - Raikwar, Sudhanshu P
AU  - Raikwar SP
AD  - Harry S. Truman Memorial Veterans 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, Smita
AU  - Zaheer S
AD  - Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
FAU - Zaheer, Asgar
AU  - Zaheer A
AUID- ORCID: 0000-0003-3344-0371
AD  - Harry S. Truman Memorial Veterans 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  - R01 NS073670/NS/NINDS NIH HHS/United States
GR  - I01BX002477/Office of Academic Affiliations, Department of Veterans Affairs/
GR  - I01 BX002477/BX/BLRD VA/United States
GR  - R01 AG048205/AG/NIA NIH HHS/United States
GR  - AG048205/National Institutes of Health/
PT  - Journal Article
DEP - 20180914
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - 0 (Beclin-1)
RN  - 0 (Biomarkers)
RN  - 0 (Glia Maturation Factor)
RN  - 0 (Protein Aggregates)
RN  - 0 (Sequestosome-1 Protein)
RN  - 0 (Sqstm1 protein, mouse)
RN  - 0 (alpha-Synuclein)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Autophagosomes/drug effects/metabolism
MH  - *Autophagy/drug effects
MH  - Beclin-1/metabolism
MH  - Biomarkers/metabolism
MH  - Cell Nucleus/drug effects/metabolism
MH  - Cells, Cultured
MH  - Dopaminergic Neurons/drug effects/enzymology/*metabolism
MH  - *Endoplasmic Reticulum Stress
MH  - Enzyme Activation/drug effects
MH  - Glia Maturation Factor/*metabolism/pharmacology
MH  - Lysosomes/drug effects/metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Protein Aggregates/drug effects
MH  - Protein Transport/drug effects
MH  - Rats
MH  - Sequestosome-1 Protein/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - alpha-Synuclein/metabolism
PMC - PMC6417980
MID - NIHMS1005359
OTO - NOTNLM
OT  - Autophagy dysfunction
OT  - Glia maturation factor
OT  - Parkinson's disease
OT  - Protein aggregation
COIS- Conflict of Interest The authors declare that there are no conflicts of interest. 
      Compliance with Ethical Standards Conflict of Interest The authors declare that 
      they have no conflicts of interest.
EDAT- 2018/09/16 06:00
MHDA- 2019/08/30 06:00
PMCR- 2019/06/01
CRDT- 2018/09/16 06:00
PHST- 2018/07/14 00:00 [received]
PHST- 2018/08/30 00:00 [accepted]
PHST- 2018/09/16 06:00 [pubmed]
PHST- 2019/08/30 06:00 [medline]
PHST- 2018/09/16 06:00 [entrez]
PHST- 2019/06/01 00:00 [pmc-release]
AID - 10.1007/s12035-018-1340-1 [pii]
AID - 10.1007/s12035-018-1340-1 [doi]
PST - ppublish
SO  - Mol Neurobiol. 2019 Jun;56(6):3865-3881. doi: 10.1007/s12035-018-1340-1. Epub 
      2018 Sep 14.