Animal studies reveal downregulation of the Beclin-1 autophagy pathway as shared mechanism in Autism Spectrum Disorder: a systematic review and meta-analysis

BACKGROUND: Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with complex etiology, involving genetic and environmental influences on brain development and behavior. Dysregulation of mammalian target of rapamycin (mTOR) signaling alters neuronal growth and synaptic plasticity, and has emerged as a potential underlying pathway in ASD. GOAL AND METHODS: To investigate mTOR dysregulation as a common mechanism in ASD, we performed a systematic review, and a meta-analysis of 192 studies examining mTOR signaling in diverse genetic and environmental animal models. RESULTS: Our random-effects model identified significant alterations in mTOR pathway-related proteins. For several proteins (p-AKT, PTEN, p-mTOR, p-EIF4e, LC3-II, p-S6K and p-S6), subgroup analyses revealed clear species-, sex-, age-, or brain region-specific effects. Interestingly, Beclin-1 was consistently downregulated across all subgroups. CONCLUSION: Our findings support mTOR-pathway dysregulation in ASD. The observed consistent downregulation of Beclin-1 highlights autophagy as a common mechanism, and provides new leads for novel ASD biomarker and treatment development.