PMID- 31837419
OWN - NLM
STAT- MEDLINE
DCOM- 20210104
LR  - 20240430
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 136
DP  - 2020 Mar
TI  - Knockdown of GADD34 in neonatal mutant SOD1 mice ameliorates ALS.
PG  - 104702
LID - S0969-9961(19)30377-8 [pii]
LID - 10.1016/j.nbd.2019.104702 [doi]
AB  - Mutations in Cu/Zn superoxide dismutase (SOD1) cause ~20% of familial ALS (FALS), 
      which comprises 10% of total ALS cases. In mutant SOD1- (mtSOD1-) induced ALS, 
      misfolded aggregates of SOD1 lead to activation of the unfolded protein 
      response/integrated stress response (UPR/ISR). Protein kinase R (PKR)-like 
      endoplasmic reticulum kinase (PERK), a kinase that phosphorylates eukaryotic 
      translation initiator factor 2alpha (p-eIF2alpha), coordinates the response by causing a 
      global suppression of protein synthesis. Growth arrest and DNA damage 34 (GADD34) 
      dephosphorylates p-eIF2alpha, allowing protein synthesis to return to normal. If the 
      UPR/ISR is overwhelmed by the amount of misfolded protein, CCAAT/enhancer-binding 
      homologous protein (CHOP) is activated leading to apoptosis. In the current study 
      we investigated the effect of knocking down CHOP and GADD34 on disease of G93A 
      and G85R mtSOD1 mice. Although a CHOP antisense oligonucleotide had no effect on 
      survival, an intravenous injection of GADD34 shRNA encoded in adeno-associated 
      virus 9 (AAV9) into neonatal G93A as well as neonatal G85R mtSOD1 mice led to a 
      significantly increased survival. G85R mtSOD1 mice had a reduction in SOD1 
      aggregates/load, astrocytosis, and microgliosis. In contrast, there was no change 
      in disease phenotype when GADD34 shRNA was delivered to older G93A mtSOD1 mice. 
      Our current study shows that GADD34 shRNA is effective in ameliorating disease 
      when administered to neonatal mtSOD1 mice. Targeting the UPR/ISR may be 
      beneficial in mtSOD1-induced ALS as well as other neurodegenerative diseases in 
      which misfolded proteins and ER stress have been implicated.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Ghadge, Ghanashyam D
AU  - Ghadge GD
AD  - Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, 
      United States of America.
FAU - Sonobe, Yoshifumi
AU  - Sonobe Y
AD  - Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, 
      United States of America.
FAU - Camarena, Adrian
AU  - Camarena A
AD  - Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, 
      United States of America.
FAU - Drigotas, Claire
AU  - Drigotas C
AD  - Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, 
      United States of America.
FAU - Rigo, Frank
AU  - Rigo F
AD  - Ionis Pharmaceuticals, Carlsbad, CA 90201, United States of America.
FAU - Ling, Karen K
AU  - Ling KK
AD  - Ionis Pharmaceuticals, Carlsbad, CA 90201, United States of America.
FAU - Roos, Raymond P
AU  - Roos RP
AD  - Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, 
      United States of America. Electronic address: rroos@neurology.bsd.uchicago.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191216
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - EC 3.1.3.16 (Ppp1r15a protein, mouse)
RN  - EC 3.1.3.16 (Protein Phosphatase 1)
RN  - EC 1.15.1.1 (Sod1 protein, mouse)
RN  - EC 1.15.1.1 (Superoxide Dismutase-1)
SB  - IM
MH  - Animals
MH  - Female
MH  - Male
MH  - Mice
MH  - *Amyotrophic Lateral Sclerosis/genetics/metabolism/prevention & control
MH  - Animals, Newborn
MH  - *Gene Knockdown Techniques/methods
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - *Protein Phosphatase 1/deficiency/genetics
MH  - *Superoxide Dismutase-1/genetics/metabolism
MH  - Disease Models, Animal
OTO - NOTNLM
OT  - Antisense oligonucleotides
OT  - CHOP
OT  - Familial amyotrophic lateral sclerosis
OT  - GADD34
OT  - Integrated stress response
OT  - Mutant Cu/Zn superoxide dismutase
OT  - Unfolded protein response
OT  - shRNA
EDAT- 2019/12/15 06:00
MHDA- 2021/01/05 06:00
CRDT- 2019/12/15 06:00
PHST- 2019/09/24 00:00 [received]
PHST- 2019/11/26 00:00 [revised]
PHST- 2019/12/08 00:00 [accepted]
PHST- 2019/12/15 06:00 [pubmed]
PHST- 2021/01/05 06:00 [medline]
PHST- 2019/12/15 06:00 [entrez]
AID - S0969-9961(19)30377-8 [pii]
AID - 10.1016/j.nbd.2019.104702 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2020 Mar;136:104702. doi: 10.1016/j.nbd.2019.104702. Epub 2019 Dec 
      16.