PMID- 34756885
OWN - NLM
STAT- MEDLINE
DCOM- 20220214
LR  - 20220214
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 297
IP  - 6
DP  - 2021 Dec
TI  - Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, 
      protecting dopaminergic neurons from manganese-induced excitotoxicity.
PG  - 101372
LID - S0021-9258(21)01178-9 [pii]
LID - 10.1016/j.jbc.2021.101372 [doi]
LID - 101372
AB  - Chronic exposure to high levels of manganese (Mn) leads to manganism, a 
      neurological disorder with similar symptoms to those inherent to Parkinson's 
      disease. However, the underlying mechanisms of this pathological condition have 
      yet to be established. Since the human excitatory amino acid transporter 2 
      (EAAT2) (glutamate transporter 1 in rodents) is predominantly expressed in 
      astrocytes and its dysregulation is involved in Mn-induced excitotoxic neuronal 
      injury, characterization of the mechanisms that mediate the Mn-induced impairment 
      in EAAT2 function is crucial for the development of novel therapeutics against Mn 
      neurotoxicity. Repressor element 1-silencing transcription factor (REST) exerts 
      protective effects in many neurodegenerative diseases. But the effects of REST on 
      EAAT2 expression and ensuing neuroprotection are unknown. Given that the EAAT2 
      promoter contains REST binding sites, the present study investigated the role of 
      REST in EAAT2 expression at the transcriptional level in astrocytes and 
      Mn-induced neurotoxicity in an astrocyte-neuron coculture system. The results 
      reveal that astrocytic REST positively regulates EAAT2 expression with the 
      recruitment of an epigenetic modifier, cAMP response element-binding 
      protein-binding protein/p300, to its consensus binding sites in the EAAT2 
      promoter. Moreover, astrocytic overexpression of REST attenuates Mn-induced 
      reduction in EAAT2 expression, leading to attenuation of glutamate-induced 
      neurotoxicity in the astrocyte-neuron coculture system. Our findings demonstrate 
      that astrocytic REST plays a critical role in protection against Mn-induced 
      neurotoxicity by attenuating Mn-induced EAAT2 repression and the ensuing 
      excitotoxic dopaminergic neuronal injury. This indicates that astrocytic REST 
      could be a potential molecular target for the treatment of Mn toxicity and other 
      neurological disorders associated with EAAT2 dysregulation.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Pajarillo, Edward
AU  - Pajarillo E
AD  - Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, 
      Florida, USA.
FAU - Digman, Alexis
AU  - Digman A
AD  - Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, 
      Florida, USA.
FAU - Nyarko-Danquah, Ivan
AU  - Nyarko-Danquah I
AD  - Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, 
      Florida, USA.
FAU - Son, Deok-Soo
AU  - Son DS
AD  - Department of Biochemistry and Cancer Biology, Meharry Medical College, 
      Nashville, Tennessee, USA.
FAU - Soliman, Karam F A
AU  - Soliman KFA
AD  - Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, 
      Florida, USA.
FAU - Aschner, Michael
AU  - Aschner M
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, 
      New York, USA; Laboratory of Molecular Nutrition of the Institute for 
      Personalized Medicine, Sechenov First Moscow State Medical University, Moscow, 
      Russia.
FAU - Lee, Eunsook
AU  - Lee E
AD  - Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, 
      Florida, USA. Electronic address: eunsook.lee@famu.edu.
LA  - eng
GR  - U54 MD007582/MD/NIMHD NIH HHS/United States
GR  - SC1 CA200519/CA/NCI NIH HHS/United States
GR  - R01 ES020852/ES/NIEHS NIH HHS/United States
GR  - R01 ES024756/ES/NIEHS NIH HHS/United States
GR  - R01 ES031282/ES/NIEHS NIH HHS/United States
GR  - R01 ES007331/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211029
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (RE1-silencing transcription factor)
RN  - 0 (Repressor Proteins)
RN  - 0 (SLC1A2 protein, human)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 42Z2K6ZL8P (Manganese)
SB  - IM
MH  - Animals
MH  - Astrocytes/metabolism
MH  - Cell Line
MH  - Dopaminergic Neurons/drug effects/*metabolism
MH  - Excitatory Amino Acid Transporter 2/genetics/*metabolism
MH  - Glutamic Acid/metabolism
MH  - Humans
MH  - Manganese/*pharmacology
MH  - Mice
MH  - Promoter Regions, Genetic
MH  - Regulatory Sequences, Nucleic Acid
MH  - Repressor Proteins/*physiology
MH  - Transcription, Genetic/physiology
MH  - Up-Regulation/*physiology
PMC - PMC8626589
OTO - NOTNLM
OT  - EAAT2
OT  - GLT-1
OT  - Parkinson's disease
OT  - RE1-silencing transcription factor
OT  - astrocyte-neuron coculture
OT  - dopaminergic neurons
OT  - excitotoxicity
OT  - manganese
OT  - neuron-restrictive silencing factor
OT  - neurotoxicity
COIS- Conflict of interest The authors declare no conflicts of interest with the 
      contents of this article.
EDAT- 2021/11/11 06:00
MHDA- 2022/02/15 06:00
PMCR- 2021/10/29
CRDT- 2021/11/10 14:31
PHST- 2021/06/07 00:00 [received]
PHST- 2021/10/18 00:00 [revised]
PHST- 2021/10/27 00:00 [accepted]
PHST- 2021/11/11 06:00 [pubmed]
PHST- 2022/02/15 06:00 [medline]
PHST- 2021/11/10 14:31 [entrez]
PHST- 2021/10/29 00:00 [pmc-release]
AID - S0021-9258(21)01178-9 [pii]
AID - 101372 [pii]
AID - 10.1016/j.jbc.2021.101372 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Dec;297(6):101372. doi: 10.1016/j.jbc.2021.101372. Epub 2021 
      Oct 29.