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Exploring the Multifactorial Nature of Autism Through Computational Systems Biology: Calcium and the Rho GTPase RAC1 Under the Spotlight

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Abstract

Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication accompanied with repetitive behavioral patterns and unusual stereotyped interests. Autism is considered a highly heterogeneous disorder with diverse putative causes and associated factors giving rise to variable ranges of symptomatology. Incidence seems to be increasing with time, while the underlying pathophysiological mechanisms remain virtually uncharacterized (or unknown). By systematic review of the literature and a systems biology approach, our aims were to examine the multifactorial nature of autism with its broad range of severity, to ascertain the predominant biological processes, cellular components, and molecular functions integral to the disorder, and finally, to elucidate the most central contributions (genetic and/or environmental) in silico. With this goal, we developed an integrative network model for gene–environment interactions (GENVI model) where calcium (Ca2+) was shown to be its most relevant node. Moreover, considering the present data from our systems biology approach together with the results from the differential gene expression analysis of cerebellar samples from autistic patients, we believe that RAC1, in particular, and the RHO family of GTPases, in general, could play a critical role in the neuropathological events associated with autism.

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Acknowledgments

First of all, we apologize to all our colleagues whose studies were not cited due to lack of space. We thank the Brazilian research funding agencies FAPERGS (PqG 1008860, PqG 1008857, ARD11/1893-7, PRONEX 1000274), CAPES (PROCAD 066/2007), CNPq, PROPESQ-UFRGS, and IBN-Net #01.06.0842-00 for supporting this work. A.B.S is supported by the grant from the Federal Program of the Russian Federation (N 8061, 2012–2013). We are very grateful to Prof. Alexei Verkhratsky (University of Manchester, Manchester, UK) and Dr. Marcio L. Acencio (Universidade Estadual Paulista, São Paulo, Brasil) for reading the manuscript.

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Center of Oxidative Stress Research, Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Fares Zeidán-Chuliá, José Luiz Rybarczyk-Filho, Ben-Hur Neves de Oliveira & José Cláudio F. Moreira

  2. Departamento de Física e Biofísica, Instituto de Biociências de Botucatu, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil

    José Luiz Rybarczyk-Filho

  3. Department of Biochemistry, Medical, Pharmaceutical and Toxicological Chemistry, Krasnoyarsk State Medical University, Krasnoyarsk, Russia

    Alla B. Salmina

  4. Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Mami Noda

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  1. Fares Zeidán-Chuliá
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Correspondence to Fares Zeidán-Chuliá.

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Zeidán-Chuliá, F., Rybarczyk-Filho, J.L., Salmina, A.B. et al. Exploring the Multifactorial Nature of Autism Through Computational Systems Biology: Calcium and the Rho GTPase RAC1 Under the Spotlight. Neuromol Med 15, 364–383 (2013). https://doi.org/10.1007/s12017-013-8224-3

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