Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder?
Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent findings have also implicated mTORC1 signaling abnormalities in a subset of nonsyndromic ASD, suggesting that defective mTORC1 pathway may be a potential converging mechanism in ASD pathology across different etiologies. However, the mechanistic evidence for a causal link between aberrant mTORC1 pathway activity and ASD neurobehavioral features varies depending on the ASD form involved. In this review, we first discuss six monogenic ASD-related syndromes, including both classical and potentially novel mTORopathies, highlighting their contribution to our understanding of the neurobiological mechanisms underlying ASD, and then we discuss existing evidence suggesting that aberrant mTORC1 signaling may also play a role in nonsyndromic ASD.
Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil. juliana.magdalon@einstein.br.
Juliana
J
Magdalon
Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil. sandra.mabel@einstein.br.|Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo 05508-090, Brazil. sandra.mabel@einstein.br.
Sandra M
SM
Sánchez-Sánchez
Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil. karina.griesi@einstein.br.
Karina
K
Griesi-Oliveira
Hospital Israelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo 05652-900, Brazil. andrea.sertie@einstein.br.
Andréa L
AL
Sertié
D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
ASD-related syndromes and nonsyndromic/idiopathic ASD; axonal and dendritic morphogenesis; dendritic spine density and maturation; mTORC1 signaling pathway; mTORC1-targeted therapies; neuronal cell growth; synaptic plasticity