The ALA5/ALA6/ALA7 repeat polymorphisms of the glutathione peroxidase-1 (GPx1) gene and autism spectrum disorder.
ALA5 variant of the antioxidant enzyme GPx1 is more common in ASD and shows reduced activity, pointing to oxidative stress as one biological piece of the autism puzzle.
01Research in Context
What this study did
The team looked at a tiny spelling change in the GPx1 gene. This gene makes an enzyme that protects cells from rust-like damage.
They compared the gene pattern in people with autism to people without autism. Lab tests checked how well each version of the enzyme worked.
What they found
The ALA5 version of the gene showed up more often in the autism group. In the test tube, that version cleaned up harmful peroxides more slowly.
Slower cleanup means the brain may face extra oxidative stress.
How this fits with other research
Melnyk et al. (2012) already saw signs of oxidative damage in kids with autism. The new study points to one reason why: their GPx1 enzyme may be sluggish.
Weiss et al. (2021) found sex-specific methylation changes in metabolic pathways. Both papers spotlight oxidative and mitochondrial biology, but at different molecular layers.
Bay et al. (2023) measured lower Neuroligin gene expression in autism. Unlike those RNA findings, Federica et al. focus on a DNA variant that changes enzyme speed, not gene amount.
Why it matters
You cannot change genes, but you can watch for stress triggers. Kids with the ALA5 pattern may tire faster during long therapy sessions. Build in short breaks, offer antioxidant-rich snacks, and track behavior changes. Share the finding with families so they can discuss antioxidant support with their doctor.
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02At a glance
03Original abstract
Autism is a severe neurodevelopmental disorder leading to deficits in social interaction, communication, and several activities. An increasing number of evidence suggests a role of oxidative stress in the etiology of autism spectrum disorder (ASD). Indeed, impaired antioxidant mechanisms may lead to the inadequate removal of H2 O2 with a consequent increase in highly active hydroxyl radicals and other reactive oxygen species causing cellular damages. The GPx1 is one of the most important enzymes counteracting oxidative stress. In this work, we investigated a possible correlation between the GCG repeat polymorphism present in the first exon of GPx1 gene encoding a tract of five to seven alanine residues (ALA5, ALA6, and ALA7) and ASD. Our findings highlighted a high frequency of ALA5 allele in ASD subjects. Moreover, proteins corresponding to the three GPx1 variants were produced in vitro, and the evaluation of their activity showed a lower values for GPx1 having ALA5 polymorphism. The comparison of the secondary and tertiary structure predictions revealed an alpha-helix in correspondence of alanine stretch only in the case of GPx1-ALA7 variant. Finally, to better investigate protein structure, steady-state fluorescence measurements of GPx1 intrinsic tryptophan were carried out and the three tested proteins exhibited a different stability under denaturing conditions. This work demonstrates the importance in adopting a multidisciplinary strategy to comprehend the role of GPx1 in ASD. LAY SUMMARY: Results here obtained suggest a possible role of ALA5 GPx1 variant in ASD. However, given the multifactorial nature of autism, this evidence might be a piece of a more complex puzzle being the GPx1 enzyme part of a complex pathway in which several proteins are involved.
Autism research : official journal of the International Society for Autism Research, 2022 · doi:10.1054/plef.2002.0439