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 and/or altered antioxidant defences. 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.

4HNE protein adducts in Autistic Spectrum Disorders: Rett syndrome and Autism

VALACCHI, Giuseppe;
In corso di stampa

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 and/or altered antioxidant defences. 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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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1728518
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