PMID- 17823119
OWN - NLM
STAT- MEDLINE
DCOM- 20071213
LR  - 20220129
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 44
DP  - 2007 Nov 2
TI  - A caspase-3-cleaved fragment of the glial glutamate transporter EAAT2 is 
      sumoylated and targeted to promyelocytic leukemia nuclear bodies in mutant 
      SOD1-linked amyotrophic lateral sclerosis.
PG  - 32480-90
AB  - EAAT2 (excitatory amino acid transporter 2) is a high affinity, Na+-dependent 
      glutamate transporter of glial origin that is essential for the clearance of 
      synaptically released glutamate and prevention of excitotoxicity. During the 
      course of human amyotrophic lateral sclerosis (ALS) and in a transgenic mutant 
      SOD1 mouse model of the disease, expression and activity of EAAT2 is remarkably 
      reduced. We previously showed that some of the mutant SOD1 proteins exposed to 
      oxidative stress inhibit EAAT2 by triggering caspase-3 cleavage of EAAT2 at a 
      single defined locus. This gives rise to two fragments that we termed truncated 
      EAAT2 and COOH terminus of EAAT2 (CTE). In this study, we report that analysis of 
      spinal cord homogenates prepared from mutant G93A-SOD1 mice reveals CTE to be of 
      a higher molecular weight than expected because it is conjugated with SUMO-1. The 
      sumoylated CTE fragment (CTE-SUMO-1) accumulates in the spinal cord of these mice 
      as early as presymptomatic stage (70 days of age) and not in other central 
      nervous system areas unaffected by the disease. The presence and accumulation of 
      CTE-SUMO-1 is specific to ALS mice, since it does not occur in the R6/2 mouse 
      model for Huntington disease. Furthermore, using an astroglial cell line, primary 
      culture of astrocytes, and tissue samples from G93A-SOD1 mice, we show that 
      CTE-SUMO-1 is targeted to promyelocytic leukemia nuclear bodies. Since one of the 
      proposed functions of promyelocytic leukemia nuclear bodies is regulation of gene 
      transcription, we suggest a possible novel mechanism by which the glial glutamate 
      transporter EAAT2 could contribute to the pathology of ALS.
FAU - Gibb, Stuart L
AU  - Gibb SL
AD  - Farber Institute for Neurosciences, Weinberg Unit for ALS Research, Thomas 
      Jefferson University, Philadelphia, Pennsylvania 19107, and Cecil B. Day 
      Laboratory for Neuromuscular Research, Massachusetts General Hospital, 
      Charlestown 02129, USA.
FAU - Boston-Howes, William
AU  - Boston-Howes W
FAU - Lavina, Zeno S
AU  - Lavina ZS
FAU - Gustincich, Stefano
AU  - Gustincich S
FAU - Brown, Robert H Jr
AU  - Brown RH Jr
FAU - Pasinelli, Piera
AU  - Pasinelli P
FAU - Trotti, Davide
AU  - Trotti D
LA  - eng
GR  - GGP06268/TI_/Telethon/Italy
GR  - R01-NS44292/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070906
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (SOD1 protein, human)
RN  - 0 (SUMO-1 Protein)
RN  - EC 1.15.1.1 (Sod1 protein, mouse)
RN  - EC 1.15.1.1 (Sod1 protein, rat)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.15.1.1 (Superoxide Dismutase-1)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Amyotrophic Lateral Sclerosis/*pathology
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Astrocytes/metabolism
MH  - Caspase 3/*metabolism
MH  - Cell Nucleus Structures/metabolism
MH  - Excitatory Amino Acid Transporter 2/chemistry/*metabolism
MH  - Humans
MH  - Huntington Disease/pathology
MH  - Immunoprecipitation
MH  - Intranuclear Inclusion Bodies/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Weight
MH  - Protein Structure, Tertiary
MH  - Rats
MH  - SUMO-1 Protein/*metabolism
MH  - Spinal Cord/pathology
MH  - Superoxide Dismutase/genetics/*metabolism
MH  - Superoxide Dismutase-1
EDAT- 2007/09/08 09:00
MHDA- 2007/12/14 09:00
CRDT- 2007/09/08 09:00
PHST- 2007/09/08 09:00 [pubmed]
PHST- 2007/12/14 09:00 [medline]
PHST- 2007/09/08 09:00 [entrez]
AID - S0021-9258(20)43074-1 [pii]
AID - 10.1074/jbc.M704314200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Nov 2;282(44):32480-90. doi: 10.1074/jbc.M704314200. Epub 2007 
      Sep 6.