PMID- 23886890
OWN - NLM
STAT- MEDLINE
DCOM- 20140312
LR  - 20231213
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 183
IP  - 3
DP  - 2013 Sep
TI  - Molecular and functional alterations in a mouse cardiac model of Friedreich 
      ataxia: activation of the integrated stress response, eIF2alpha phosphorylation, and 
      the induction of downstream targets.
PG  - 745-57
LID - S0002-9440(13)00455-0 [pii]
LID - 10.1016/j.ajpath.2013.05.032 [doi]
AB  - Friedreich ataxia (FA) is a neurodegenerative and cardiodegenerative disease 
      resulting from marked frataxin deficiency. The condition is characterized by 
      ataxia with fatal cardiomyopathy, but the pathogenic mechanisms are unclear. We 
      investigated the association between gene expression and progressive 
      histopathological and functional changes using the muscle creatine kinase 
      conditional frataxin knockout (KO) mouse; this mouse develops a severe cardiac 
      phenotype that resembles that of FA patients. We examined KO mice from 3 weeks of 
      age, when they are asymptomatic, to 10 weeks of age, when they die of the 
      disease. Positive iron staining was identified in KO mice from 5 weeks of age, 
      with markedly reduced cardiac function from 6 weeks. We identified an early and 
      marked up-regulation of a gene cohort responsible for stress-induced amino acid 
      biosynthesis and observed markedly increased phosphorylation of eukaryotic 
      translation initiation factor 2alpha (p-eIF2alpha), an activator of the integrated stress 
      response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, 
      the eIF2alpha-mediated integrated stress response has been previously implicated in 
      heart failure via downstream processes such as autophagy and apoptosis. Indeed, 
      expression of a panel of autophagy and apoptosis markers was enhanced in KO mice. 
      Thus, the pathogenesis of cardiomyopathy in FA correlates with the early and 
      persistent eIF2alpha phosphorylation, which precedes activation of autophagy and 
      apoptosis.
CI  - Copyright (c) 2013 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Huang, Michael Li-Hsuan
AU  - Huang ML
AD  - Molecular Pharmacology and Pathology Program, Department of Pathology, University 
      of Sydney, Sydney, Australia.
FAU - Sivagurunathan, Sutharshani
AU  - Sivagurunathan S
FAU - Ting, Samantha
AU  - Ting S
FAU - Jansson, Patric J
AU  - Jansson PJ
FAU - Austin, Christopher J D
AU  - Austin CJ
FAU - Kelly, Matthew
AU  - Kelly M
FAU - Semsarian, Christopher
AU  - Semsarian C
FAU - Zhang, Daohai
AU  - Zhang D
FAU - Richardson, Des R
AU  - Richardson DR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130722
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Amino Acids)
RN  - 0 (Atf4 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Iron-Binding Proteins)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - EC 2.7.- (Protein Kinases)
SB  - IM
MH  - Activating Transcription Factor 4/metabolism
MH  - Amino Acids/biosynthesis
MH  - Animals
MH  - Apoptosis
MH  - Autophagy
MH  - Cardiomegaly/pathology/physiopathology
MH  - Disease Models, Animal
MH  - Eukaryotic Initiation Factor-2/*metabolism
MH  - Female
MH  - Friedreich Ataxia/diagnostic imaging/*genetics/*pathology/physiopathology
MH  - Gene Expression Profiling
MH  - Heart Function Tests
MH  - Humans
MH  - Iron-Binding Proteins/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Myocardium/metabolism/pathology
MH  - Myocytes, Cardiac/enzymology/pathology
MH  - Phenotype
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - *Signal Transduction/genetics
MH  - *Stress, Physiological/genetics
MH  - Ultrasonography
MH  - Frataxin
EDAT- 2013/07/28 06:00
MHDA- 2014/03/13 06:00
CRDT- 2013/07/27 06:00
PHST- 2013/03/27 00:00 [received]
PHST- 2013/05/16 00:00 [revised]
PHST- 2013/05/31 00:00 [accepted]
PHST- 2013/07/27 06:00 [entrez]
PHST- 2013/07/28 06:00 [pubmed]
PHST- 2014/03/13 06:00 [medline]
AID - S0002-9440(13)00455-0 [pii]
AID - 10.1016/j.ajpath.2013.05.032 [doi]
PST - ppublish
SO  - Am J Pathol. 2013 Sep;183(3):745-57. doi: 10.1016/j.ajpath.2013.05.032. Epub 2013 
      Jul 22.