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

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 (Ca(2+)) 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.

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

“…Several other autism-risk genes, such as Nlg1, Nrx-4, P-Rex1, and Shank-3, have also been reported to participate in the Rac1-signaling pathway (61)(62)(63)(64). In addition, when the gene-environment interactions of 122 genes and 191 factors in the autistic context were analyzed by systems biology, Rac1 was predicted to be a converging node that genetically links to the neurobiology of autism (27,65)…”

“…Thus, the inability to evoke Rac1-dependent forgetting causes behavioral inflexibility in transgenic flies, and the inability to forget may cause behavioral inflexibility in autism patients. Second, a systems biology analysis concludes that Rac1 plays a critical role in the neuropathological events associated with autism based on gene-expression analysis of cerebellar samples from patients with autism (27). Thus, we were led to investigate whether Rac1-dependent forgetting is a converging function of homologs of autism-risk genes.…”

Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q

“…Guerin et al 10 described a single patient with a 2.89-Mb deletion in distal 11q who had autistic features and proposed the Kirrel3 gene as a candidate for causing autism in the patient. ASD results from a large variety of genetic causes 30,31 and the results from the current study add to the growing list of genetic syndromes associated with a proportion of children who have ASD. 32 Original research article…”

“…35 ARHGAP32 (formerly RICS) encodes a neuronassociated GTPase-activating protein that regulates dendritic spine morphology and strength by modulating Rho GTPase. 31,36 Studies of mice revealed that ARHGAP32 is involved in early brain development, including extension of axons and dendrites, and postnatal remodeling and fine-tuning of neural circuits. 37 To date, nothing is known about the role of ARHGAP32 in cognition or behavior.…”

RGK regulation of voltage-gated calcium channels

“…Thus, while a role for Ca 2+ ions may be excluded in the reduced dendritic arborization of TS cells, it cannot be disregarded in contributing to the overall autistic phenotype in TS patients. A recent combination of systems and computational approaches suggested Ca 2+ as a central factor in the pathophysiology of autism [54].…”