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Altered mTORC1 signaling in multipotent stem cells from nearly 25% of patients with nonsyndromic autism spectrum disorders

Molecular Psychiatry volume 20, pages 551–552 (2015)Cite this article

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Recent autism spectrum disorders (ASD) research supports a model wherein disinhibited mTORC1 signaling and dysregulated protein synthesis in neurons contribute to the clinical features of ASD, mainly through disturbances in synaptic connectivity and plasticity.1, 2 Most insights into this pathomechanism came from ASD-related monogenic syndromes caused by loss of function mutations in negative regulators of PI3K-mTOR pathway (such as TSC1/TSC2, tuberous sclerosis syndrome; FMR1, fragile-X syndrome).3, 4 In addition, it has been recently reported aberrant mTORC1-dependent translation in a mouse model for nonsyndromic ASD (eIF4E).5 However, functional studies addressing mTORC1-signaling activity in accessible sources of cells from patients with nonsyndromic ASD are lacking. In this study we have made use of the cultured stem cells from human exfoliated deciduous teeth (SHEDs) derived from nonsyndromic ASD patients, a model system that, albeit non-neural, we have recently shown to be suitable to explore dysregulated pathways and biological processes in ASD,6 to investigate this important and yet poorly explored question.

In accordance with the hyperresponsive mTORC1 signaling, growth curves of ASD1–3 SHEDs in response to different fetal bovine serum concentrations showed that these cells could be clearly distinguished from the other samples analyzed, and displayed a 1.5–2-fold greater increase in cell number, mainly at the later time points of the curve (Figure 1b, Supplementary Figure 1b), and reduced response to the antiproliferative effect of rapamycin, a specific mTOR inhibitor (Figure 1c, Supplementary Figure 1c). Curiously, whereas dual PI3K-mTOR inhibition (wortmannin+rapamycin treatment) continued to be less effective in reducing to a similar extent the proliferation of ASD1–2 and control cells, it was able to restore the enhanced proliferation of ASD3 cells (Figure 1c, Supplementary Figure 1c), suggesting a possible different regulatory mechanism in ASD3 cells. Knockout mouse models of both syndromic and nonsyndromic ASD with disinhibited mTOR signaling and dysregulated protein synthesis present dysplastic and enlarged neurons with increased spine density in several brain regions.5, 7, 8 Although we did not notice increased ASD1–3 SHED volumes, it will now be important to determine and explore further whether the altered proliferative phenotype observed in these cells may also be observed in neuronal cell types, which could be a potential additional mechanism whereby disrupted mTORC1 signaling contributes to ASD neuropathology.

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Authors and Affiliations

  1. Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil,

    A M Suzuki, K Griesi-Oliveira, E C Zachi & M R Passos-Bueno

  2. Hospital lsraelita Albert Einstein, Centro de Pesquisa Experimental, São Paulo, Brasil,

    K Griesi-Oliveira, C de Oliveira Freitas Machado & A L Sertie

  3. Instituto de Psiquiatria, Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil

    E Vadasz

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  1. A M Suzuki
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  2. K Griesi-Oliveira
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Correspondence to A L Sertie.

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Suzuki, A., Griesi-Oliveira, K., de Oliveira Freitas Machado, C. et al. Altered mTORC1 signaling in multipotent stem cells from nearly 25% of patients with nonsyndromic autism spectrum disorders. Mol Psychiatry 20, 551–552 (2015). https://doi.org/10.1038/mp.2014.175

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