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Biophysics

Biophysics

Cytoskeleton dynamics help reveal mechanisms of autism

21 Aug 2018 Salomé Guillaumin 
Actin re-polymerization
Left: depolymerized actin filaments; right: one hour after treatment to induce repolymerization. More cells presented repolymerized actin filaments in the control group compared with the ASD individual, suggesting that repolymerization is slower in ASD patients. (Courtesy: Scientific Reports 8 11138/CC BY 4.0)

Autism spectrum disorder (ASD) is a condition comprising behavioural and developmental problems that affect the communication, social and interaction skills of the patient. According to the World Health Organization (WHO), this pathology affects one in 160 children worldwide, with three times more males affected than females, and it’s been increasing globally over the last 50 years.

From a genetic perspective, different gene modifications exist in ASD patients, but only 25% of them have been identified. To develop a therapy, however, we need to identify targets – the genes involved in the disease. As a consequence, more studies are essential to understand and develop a cure for this disease.

With this aim, Maria Rita Passos-Bueno and her team at the University of São Paulo investigated a protein named actin, which is the most abundant protein in our cells and is involved in many structural and functional roles, including cell motility and cell division for cell proliferation (Scientific Reports 8 11138).

Actin is present as filaments in the cytoskeleton of cells. To achieve their functions, these actin filaments are subject to polymerization and depolymerization processes. In the brain, the correct regulation of this polymerization/depolymerization dynamic is essential to sculpt neuronal connectivity.

Karina Griesi-Oliveira

In this study, the group investigated actin filament reconstitution under stimulation of RhoGTPase (the main group of molecules involved in actin polymerization), in stem cells obtained from the exfoliated deciduous teeth (SHEDs) of 13 ASD patients and eight controls (non-ASD patients).

The researchers used an inhibitor of RhoGTPase to induce actin depolymerization, and promoted repolymerization using a direct activator (DA) that simultaneously activates three molecules involved in repolarization: Cdc42, Rac and RhoA. Those proteins were also activated separately using epidermal growth factor (Cdc42 and Rac) or calpectin (Rho) in order to activate upstream signals.

From the 13 ASD patients studied, only a subgroup of seven patients’ cells behaved differently to the control group, with different responses depending upon the pharmacological treatment. This group of seven ASD patients showed a lower percentage of cells with reconstituted actin filaments.

Polymerization pathway

The researchers studied the possible genetic alterations in downstream or upstream molecules using the four different pharmacologic treatments. Out of the seven patients, two were presumed to have a genetic alteration in an upstream molecule and two were presumed to have a downstream genetic alteration. The origin of alterations in the three other patients couldn’t be determined. This means that, in patients with alteration in actin dynamics, the genetic origin of this alteration isn’t always the same.

SHEDs might provide a useful model to study genetic alteration, as they may reflect altered neuronal phenotypes. Prior clustering of patients was essential in this study as only a subgroup of ASD patients had an altered actin polymerization dynamic. This paper emphasizes the multiple possible genetic alterations in ASD patients. Further investigations to identify targets that could benefit many patients would be of great interest.

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