Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

Daoyin Dong, Horst Ronald Zielke, David Yeh, Peixin Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The molecular pathogenesis of autism spectrum disorder, a neurodevelopmental disorder, is still elusive. In this study, we investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. This study compared the activation of ER stress signals (protein kinase R-like endoplasmic reticulum kinase [PERK], activating transcription factor 6 [ATF6], inositol-requiring enzyme 1 alpha [IRE1α]) in different brain regions (prefrontal cortex, hippocampus, cerebellum) in subjects with autism and in age-matched controls. Our data showed that the activation of three signals of ER stress varies in different regions of the autistic brain. IRE1α was activated in cerebellum and prefrontal cortex but ATF6 was activated in hippocampus. PERK was not activated in the three regions. Furthermore, the activation of ER stress was confirmed because the expression of C/EBP-homologous protein (CHOP), which is the common downstream indicators of ER stress signals, and most of ER chaperones were upregulated in the three regions. Consistent with the induction of ER stress, apoptosis was found in the three regions by detecting the cleavage of caspase 8 and poly(ADP-ribose) polymerase as well as using the transferase dUTP nick end labeling assay. Moreover, our data showed that oxidative stress was responsible for ER stress and apoptosis because the levels of 4-Hydroxynonenal and nitrotyrosine-modified proteins were significantly increased in the three regions. In conclusion, these data indicate that cellular stress and apoptosis may play important roles in the pathogenesis of autism. Autism Res 2018, 11: 1076–1090.

Original languageEnglish (US)
Pages (from-to)1076-1090
Number of pages15
JournalAutism Research
Volume11
Issue number7
DOIs
StatePublished - Jul 2018

Keywords

  • apoptosis
  • cerebellum
  • endoplasmic reticulum stress
  • hippocampus
  • human autism
  • oxidative stress
  • prefrontal cortex

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Genetics(clinical)

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