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4HNE Protein Adducts in Autistic Spectrum Disorders: Rett Syndrome and Autism

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Comprehensive Guide to Autism

Abstract

Autistic spectrum disorders (ASDs) are a complex group of neurodevelopment disorders, still poorly understood and treatment refractory. They are considered to be the result of a complex interaction between a genetic background and environmental factors and appear to be steadily increasing in frequency, although the reasons for this increase remain partially unexplained.

Oxidative stress (OS) is a well-known pathogenic mechanism involved in several human pathologies. By definition, OS occurs when the antioxidant response is insufficient to balance the production of reactive oxygen species (ROS) leading to cell damage and developing or worsening of several pathologies.

Brain is particularly vulnerable to ROS damage compared to other organs, due to its high metabolic rate combined with a relatively low concentration of antioxidant proteins. OS and mitochondrial dysfunction have been implicated in all major neurodegenerative disorders (i.e., amyotrophic lateral sclerosis, Parkinson’s and Alzheimer’s disease), and a potential relationship between OS and ASDs has been repeatedly explored and generally found to be related to either increased OS or altered antioxidant defenses.

Nevertheless, even if several OS biomarkers have been the focus of researches on ASDs, only recent works from our group were able to show the increased levels of 4-hydroxynonenal protein adducts (4HNE PAs) in both classic autism and Rett syndrome (RTT), two of neurodevelopmental disorders that are part of the complex group of ASDs.

4HNE is an aldehyde end product generated by peroxidation of the most abundant class of ω-6 polyunsaturated fatty acids (PUFAs), and its reactivity is due to α,β-double bond. In consequence of its ability to covalently bind proteins, phospholipids, and DNA, it is recognized as “second toxic messenger” of free radicals. Oxidative protein modifications by 4HNE possess the potential to have serious detrimental effects in living organisms since they lead to alteration in their structure and biological activity, having also the potential to form cross-links in proteins.

4HNE PAs are observed in typical and atypical RTT and their levels change as a function of the time (clinical stages of typical form) and of phenotype severity (different clinical variants). Moreover, a systemic oxidant status with increased 4HNE PAs levels is also detected in classic autistic disorder. Thus, our researches showed that OS, i.e., 4HNE PAs, is present in both classic autism and RTT and that oxidative protein damage could play a key role in the pathogenic mechanisms of ASDs.

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Authors and Affiliations

  1. Department of Life Science and Biotechnologies, University of Ferrara, Via Borsari, 46, 44121, Ferrara, Italy

    Giuseppe Valacchi

  2. Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro, 2, 53100, Siena, Italy

    Alessandra Pecorelli, Cinzia Signorini, Silvia Leoncini & Lucia Ciccoli

  3. Neonatal Intensive Care Unit, University Hospital, Azienda Ospedaliera Universitaria Senese, Siena, Italy

    Claudio De Felice

  4. Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese, Viale M. Bracci, 16, 53100, Siena, Italy

    Joussef Hayek

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  1. Giuseppe Valacchi
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  2. Alessandra Pecorelli
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  3. Cinzia Signorini
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  4. Silvia Leoncini
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  7. Joussef Hayek
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Correspondence to Giuseppe Valacchi .

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Editors and Affiliations

  1. Department of Biomedical Sciences, University of Westminster, Faculty of Science & Technology, London, United Kingdom

    Vinood B. Patel

  2. Nutritional Sciences Division and Genomics Centre, King's College London, London, United Kingdom

    Victor R. Preedy

  3. Faculty of Society and Health, Buckinghamshire New University, Middlesex, United Kingdom

    Colin R. Martin

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Valacchi, G. et al. (2014). 4HNE Protein Adducts in Autistic Spectrum Disorders: Rett Syndrome and Autism. In: Patel, V., Preedy, V., Martin, C. (eds) Comprehensive Guide to Autism. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4788-7_199

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