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

Abstract

Autism results in significant morbidity and mortality in children. The functional and molecular changes in the autistic brains are unclear. The present study utilized autistic brain tissues from the National Institute of Child Health and Human Development's Brain Tissue Bank for the analysis of cellular and molecular changes in autistic brains. Three key brain regions, the hippocampus, the cerebellum, and the frontal cortex, in six cases of autistic brains and six cases of non-autistic brains from 6 to 16 years old deceased children, were analyzed. The current study investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. The activation of three signals of ER stress (protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1 alpha) varies in different regions. The occurrence of ER stress leads to apoptosis in autistic brains. ER stress may result from oxidative stress because of elevated levels of the oxidative stress markers: 4-Hydroxynonenal and nitrotyrosine-modified proteins in autistic brains. These findings suggest that cellular stress and apoptosis may contribute to the autistic phenotype. Pharmaceuticals and/or dietary supplements, which can alleviate ER stress, oxidative stress and apoptosis, may be effective in ameliorating adverse phenotypes associated with autism.

Allogeneic Human Umbilical Cord Mesenchymal Stem Cells for the Treatment of Autism Spectrum Disorder in Children: Safety Profile and Effect on Cytokine Levels

“…In particular, intestinal immune dysregulation [14] and gastrointestinal symptoms have been observed in children with ASD [15][16][17][18][19]. Furthermore, brain inflammation may be linked to the pathogenesis of neuropsychiatric disorders such as ASD [20], as observed through findings that indicate neurological inflammation, including neural fiber formation [21], enhanced oxidative stress [22], apoptosis [23], and high secretion of amyloid protein breakdown products [24]. The relationship between inflammation and autism was further evidenced in a study by Al-Ayadhi and Mostafa, in which children with ASD were found to score higher than neurotypical children in measures of macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC).…”

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

“…These results corroborated the use of primary human fibroblasts to perform our investigations, indicating that the oxidative damage is not confined only to the blood, but is also present at cell/tissue level. Indeed, in a recent report, Dong and colleagues 19 showed increased levels of 4‐HNE modified proteins in different regions of the autistic brains (ie, cerebellum, prefrontal cortex and hippocampus), where the oxidative damage was associated with the activation of endoplasmic reticulum stress and apoptosis signals, other possible molecular mechanisms underlying ASD.…”

NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models

“…Furthermore, abnormal apoptosis in the early developing brain has been suggested as a possible mechanism for the decreased number of neurons observed in individuals with autism and schizophrenia [62,88,89]. For example, increased apoptosis was observed in both postmortem brain tissue from autism patients [90] and primary fibroblasts from schizophrenia patients [91,92]. We found further support for the role of apoptosis in these disorders by identifying significant enrichments for genes associated with apoptotic processes among candidate genes for autism (empirical p<1.00×10 −5 ) [77], intellectual disability (p<1.00×10 −5 ) [93], and schizophrenia (p = 0.014) [76] (S11 Table).…”