Na⁺, K⁺‐ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells

Abstract

Na+, K+‐ATPase (NKA) activity, which establishes the sodium and potassium gradient across the cell membrane and is instrumental in the propagation of the nerve impulses, is altered in a number of neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD). In the present work, we examined a wide range of biochemical and cellular parameters in the attempt to understand the reason(s) for the severe decrease in NKA activity in erythrocytes of ASD children that we reported previously. NKA activity in leukocytes was found to be decreased independently from alteration in plasma membrane fluidity. The different subunits were evaluated for gene expression in leukocytes and for protein expression in erythrocytes: small differences in gene expression between ASD and typically developing children were not apparently paralleled by differences in protein expression. Moreover, no gross difference in erythrocyte plasma membrane oxidative modifications was detectable, although oxidative stress in blood samples from ASD children was confirmed by increased expression of NRF2 mRNA. Interestingly, gene expression of some NKA subunits correlated with clinical features. Excess inhibitory metals or ouabain‐like activities, which might account for NKA activity decrease, were ruled out. Plasma membrane cholesterol, but not phosphatidylcholine and phosphatidlserine, was slighty decreased in erythrocytes from ASD children. Although no compelling results were obtained, our data suggest that alteration in the erytrocyte lipid moiety or subtle oxidative modifications in NKA structure are likely candidates for the observed decrease in NKA activity. These findings are discussed in the light of the relevance of NKA in ASD. Autism Res 2018, 11: 1388–1403. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.Lay SummaryThe activity of the cell membrane enzyme NKA, which is instrumental in the propagation of the nerve impulses, is severely decreased in erythrocytes from ASD children and in other brain disorders, yet no explanation has been provided for this observation. We strived to find a biological/biochemical cause of such alteration, but most queries went unsolved because of the complexity of NKA regulation. As NKA activity is altered in many brain disorders, we stress the relevance of studies aimed at understanding its regulation in ASD.

Risk and Protective Environmental Factors Associated with Autism Spectrum Disorder: Evidence-Based Principles and Recommendations

“…Actually, beyond some general environmental aspects, which have been shown to be protective, such as an inclusive educational environment or a positive parenting, in the last few years, a number of peripheral markers have been identified in children affected by idiopathic autism, including altered redox balance and mitochondrial dysfunction [150], decreased DHA and cholesterol with impaired Na + /K + -ATPase activity in erythrocyte membranes [151,152], upregulation of inflammatory cytokines and dysfunctional microbiota [153,154], and a characteristic metabolomic signature [136,155]. These altered parameters not only may provide tools for early diagnosis, but should be regarded as hubs of a network of inter-related dysfunctions, which are the basis for the manifestation of autistic clinical symptoms and its more common comorbidities.…”

Plasma peroxiredoxin changes and inflammatory cytokines support the involvement of neuro-inflammation and oxidative stress in Autism Spectrum Disorder

“…Indeed, children with ASD bear hallmarks of abnormalities in systemic redox balance [21–24] as well as of increase in soluble makers of inflammation [25, 26]. Using red cells as cell model to explore oxidative stress in ASD, we reported abnormal red cell membrane lipid composition, reflecting increased pro-oxidant environment in ASD subjects [23], and, more recently, the presence of advanced glycation end-products in plasma and urine of ASD children and the up-regulation of pro-inflammatory and anti-oxidant systems in isolated polymorphonuclear cells [27, 28].…”

Fluoride Exposure Induces Inhibition of Sodium-and Potassium-Activated Adenosine Triphosphatase (Na+, K+-ATPase) Enzyme Activity: Molecular Mechanisms and Implications for Public Health

“…Furthermore, in this current study, I have provided compelling evidence that NKA activity is vital for normal brain development and loss of NKA activity is associated with cognitive impairment, neurological and developmental disorders [14,15,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86]. Indeed, loss of NKA activity represents an interconnected molecular function in neurodevelopmental and neuropsychiatric and neurodegenerative disorders including; Down syndrome, Alzheimer’s, Parkinson’s and Huntington’s disease, as well as epilepsy, autism, schizophrenia, mood and depressive disorders.…”

“…Furthermore, a great body of evidence associates neurotoxicity with a reduction of NKA activity, suggesting that reduction in NKA activity may be a link between several common neurotoxic mechanisms [14,15,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79]. Loss of NKA is associated with autism [65,66,69]; Alzheimer’s disease [66,80,81]; Parkinson’s disease [82]; amyotrophic lateral sclerosis [70,82]; Down syndrome and Huntington’s disease [69]; depression and mood disorders [71,72,73,74]; bipolar disorder [14,75,76] and schizophrenia [15,77,79], as well as in animal models of depression [83,84].…”