Abstract
Autism spectrum disorder (ASD) is a behaviorally defined disorder affecting 1 in 68 children. Currently, there is no known cause for the majority of ASD cases nor are there physiological diagnostic tools or biomarkers to aid behavioral diagnosis. Whole-genome linkage studies, genome-wide association studies, copy number variation screening, and SNP analyses have identified several ASD candidate genes, but which vary greatly among individuals and family clusters, suggesting that a variety of genetic mutations may result in a common pathology or alter a common mechanistic pathway. The Akt/mammalian target of rapamycin (mTOR) pathway is involved in many cellular processes including synaptic plasticity and immune function that can alter neurodevelopment. In this study, we examined the activity of the Akt/mTOR pathway in cells isolated from children with ASD and typically developing controls. We observed higher activity of mTOR, extracellular receptor kinase, and p70S6 kinase and lower activity of glycogen synthase kinase 3 (GSK3)α and tuberin (TSC2) in cells from children with ASD. These data suggest a phosphorylation pattern indicative of higher activity in the Akt/mTOR pathway in children with general/idiopathic ASD and may suggest a common pathological pathway of interest for ASD.
Highlights
Autism spectrum disorder (ASD) is characterized by severe and pervasive impairment in reciprocal social interaction skills, communication skills, or the presence of stereotyped behavior, interests, and activities [1]
Increased Akt/ Mammalian target of rapamycin (mTOR) activity is consistent with deficiencies of FMR1, TSC1/2, or phosphatase and tensin homolog (PTEN) found in Fragile X, TSC, and Cowden syndrome and suggests that increased Akt/mTOR activity may have a role in the pathophysiology of the general ASD population and not limited to single ASD genetic mutations
Given that Akt/mTOR genetic mutations are potentially associated with increased ASD risk, we hypothesized that aberrations in many parts of the Akt/mTOR pathway will contribute to an overall pattern of increased Akt/mTOR pathway activity
Summary
Autism spectrum disorder (ASD) is characterized by severe and pervasive impairment in reciprocal social interaction skills, communication skills, or the presence of stereotyped behavior, interests, and activities [1]. There is evidence to suggest that the disorder is highly heritable, no single genetic cause for all ASD has been identified. Several single-gene mutation syndromic disorders incur increased risk of developing ASD including Rett syndrome (MeCP2), Fragile X (FMR1), Tuberous sclerosis (either TSC1 or TSC2), Cowden syndrome (PTEN), Timothy syndrome (CACNA1C), and Angelman syndrome (UBE3A) [17,18,19]. Among the potential candidate genes identified in ASD to date, those involved in Akt/mammalian target of rapamycin (mTOR) signaling and the downstream effects of this pathway are highly represented including FMR1, PTEN, TSC1, and TSC2 [20]. We hypothesized that there are a diverse collection of physiological abnormalities including genetic mutation or environment factors that converge to dysregulate the Akt/mTOR pathway in individuals with ASD. We describe a dysregulation of Akt/mTOR signaling in T cells isolated from children with ASD compared with TD control children, data that might help point to possible etiological mechanisms in ASD
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