Molecular and functional alterations in a mouse cardiac model of friedreich ataxia: Activation of the integrated stress response, eIF2α phosphorylation, and the induction of downstream targets

Journal article


Huang, Michael Li-Hsuan, Sivagurunathan, Sutharshani, Ting, Samantha, Jansson, Patric J., Austin, Christopher J. D., Kelly, Matthew, Semsarian, Christopher, Zhang, Daohai and Richardson, Des R.. (2013). Molecular and functional alterations in a mouse cardiac model of friedreich ataxia: Activation of the integrated stress response, eIF2α phosphorylation, and the induction of downstream targets. American Journal of Pathology. 183(3), pp. 745 - 757. https://doi.org/10.1016/j.ajpath.2013.05.032
AuthorsHuang, Michael Li-Hsuan, Sivagurunathan, Sutharshani, Ting, Samantha, Jansson, Patric J., Austin, Christopher J. D., Kelly, Matthew, Semsarian, Christopher, Zhang, Daohai and Richardson, Des R.
Abstract

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 2α (p-eIF2α), an activator of the integrated stress response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, the eIF2α-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 eIF2α phosphorylation, which precedes activation of autophagy and apoptosis.

Year2013
JournalAmerican Journal of Pathology
Journal citation183 (3), pp. 745 - 757
PublisherElsevier Inc.
ISSN0002-9440
Digital Object Identifier (DOI)https://doi.org/10.1016/j.ajpath.2013.05.032
Scopus EID2-s2.0-84880074199
Page range745 - 757
Research GroupSchool of Behavioural and Health Sciences
Publisher's version
File Access Level
Controlled
Grant IDNHMRC/571123
NHMRC/632698
Place of publicationUnited States of America
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