PMID- 30007309
OWN - NLM
STAT- MEDLINE
DCOM- 20190717
LR  - 20240207
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Print)
IS  - 0006-8950 (Linking)
VI  - 141
IP  - 9
DP  - 2018 Sep 1
TI  - Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral 
      sclerosis.
PG  - 2561-2575
LID - 10.1093/brain/awy182 [doi]
AB  - We recently demonstrated that microRNA-218 (miR-218) is greatly enriched in motor 
      neurons and is released extracellularly in amyotrophic lateral sclerosis model 
      rats. To determine if the released, motor neuron-derived miR-218 may have a 
      functional role in amyotrophic lateral sclerosis, we examined the effect of 
      miR-218 on neighbouring astrocytes. Surprisingly, we found that extracellular, 
      motor neuron-derived miR-218 can be taken up by astrocytes and is sufficient to 
      downregulate an important glutamate transporter in astrocytes [excitatory amino 
      acid transporter 2 (EAAT2)]. The effect of miR-218 on astrocytes extends beyond 
      EAAT2 since miR-218 binding sites are enriched in mRNAs translationally 
      downregulated in amyotrophic lateral sclerosis astrocytes. Inhibiting miR-218 
      with antisense oligonucleotides in amyotrophic lateral sclerosis model mice 
      mitigates the loss of EAAT2 and other miR-218-mediated changes, providing an 
      important in vivo demonstration of the relevance of microRNA-mediated 
      communication between neurons and astrocytes. These data define a novel mechanism 
      in neurodegeneration whereby microRNAs derived from dying neurons can directly 
      modify the glial phenotype and cause astrocyte dysfunction.
FAU - Hoye, Mariah L
AU  - Hoye ML
AD  - Department of Neurology, Washington University School of Medicine; St. Louis, MO, 
      USA.
FAU - Regan, Melissa R
AU  - Regan MR
AD  - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 
      MD, USA.
FAU - Jensen, Leah A
AU  - Jensen LA
AD  - Department of Neurology, Washington University School of Medicine; St. Louis, MO, 
      USA.
FAU - Lake, Allison M
AU  - Lake AM
AD  - Department of Genetics, Washington University School of Medicine; St. Louis, MO, 
      USA.
AD  - Department of Psychiatry, Washington University School of Medicine; St. Louis, 
      MO, USA.
FAU - Reddy, Linga V
AU  - Reddy LV
AD  - Department of Neurology, Washington University School of Medicine; St. Louis, MO, 
      USA.
FAU - Vidensky, Svetlana
AU  - Vidensky S
AD  - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 
      MD, USA.
FAU - Richard, Jean-Philippe
AU  - Richard JP
AD  - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 
      MD, USA.
FAU - Maragakis, Nicholas J
AU  - Maragakis NJ
AD  - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 
      MD, USA.
FAU - Rothstein, Jeffrey D
AU  - Rothstein JD
AD  - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 
      MD, USA.
FAU - Dougherty, Joseph D
AU  - Dougherty JD
AD  - Department of Genetics, Washington University School of Medicine; St. Louis, MO, 
      USA.
AD  - Department of Psychiatry, Washington University School of Medicine; St. Louis, 
      MO, USA.
FAU - Miller, Timothy M
AU  - Miller TM
AD  - Department of Neurology, Washington University School of Medicine; St. Louis, MO, 
      USA.
LA  - eng
GR  - F31 NS092340/NS/NINDS NIH HHS/United States
GR  - K08 NS074194/NS/NINDS NIH HHS/United States
GR  - T35 HL007815/HL/NHLBI NIH HHS/United States
GR  - R01 NS078398/NS/NINDS NIH HHS/United States
GR  - R24 NS086741/NS/NINDS NIH HHS/United States
GR  - R01 NS102272/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Amino Acid Transport System X-AG)
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (MIRN218 microRNA, human)
RN  - 0 (MIRN218 microRNA, mouse)
RN  - 0 (MicroRNAs)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
CIN - Nat Rev Neurol. 2018 Oct;14(10):572. PMID: 30050128
CIN - Brain. 2018 Sep 1;141(9):2534-2536. PMID: 30169589
MH  - Amino Acid Transport System X-AG/genetics/physiology
MH  - Amyotrophic Lateral Sclerosis/*genetics
MH  - Animals
MH  - Astrocytes/metabolism/*physiology
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Excitatory Amino Acid Transporter 2/genetics/physiology
MH  - Glutamic Acid/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/genetics/*metabolism/physiology
MH  - Motor Neurons/metabolism/physiology
MH  - Neuroglia/metabolism
PMC - PMC6113638
EDAT- 2018/07/15 06:00
MHDA- 2019/07/18 06:00
PMCR- 2019/09/01
CRDT- 2018/07/15 06:00
PHST- 2018/01/07 00:00 [received]
PHST- 2018/05/24 00:00 [accepted]
PHST- 2018/07/15 06:00 [pubmed]
PHST- 2019/07/18 06:00 [medline]
PHST- 2018/07/15 06:00 [entrez]
PHST- 2019/09/01 00:00 [pmc-release]
AID - 5051677 [pii]
AID - awy182 [pii]
AID - 10.1093/brain/awy182 [doi]
PST - ppublish
SO  - Brain. 2018 Sep 1;141(9):2561-2575. doi: 10.1093/brain/awy182.