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Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell

Carlo Cervellati1, Claudia Sticozzi2, Arianna Romani1

  • 1Department of Biomedical and Specialist Surgical Sciences, Section of Medical Biochemistry, Molecular Biology and Genetics, University of Ferrara, Ferrara, Italy.

Biochimica Et Biophysica Acta
|July 21, 2015
PubMed

Insights

Oxidative stress (OS) in Rett syndrome (RTT) stems from increased oxidants and impaired defense mechanisms. This study reveals elevated H2O2, NOX activation, and mitochondrial dysfunction in RTT cells, contributing to redox imbalance.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Rett syndrome (RTT) is a rare neurodevelopmental disorder primarily affecting females.
  • A strong correlation between oxidative stress (OS) and RTT is documented, but its source and redox imbalance effects remain unclear.

Purpose of the Study:

  • To investigate the sources of OS and the impact of redox imbalance in RTT.
  • To analyze cellular mechanisms contributing to OS in RTT patients.

Main Methods:

  • Analysis of skin fibroblasts from RTT patients and healthy controls.
  • Measurement of hydrogen peroxide (H2O2) and 4-hydroxynonenal (HNE) protein adducts.
  • Assessment of NADPH-oxidase (NOX) activity, mitochondrial function, and proteasome activity.
  • Enzyme activity assays for glutathione peroxidase, superoxide dismutase, and thioredoxin reductases.

Main Results:

  • RTT fibroblasts exhibited elevated H2O2 and HNE protein adducts.
  • Constitutive activation of NOX was observed in RTT cells, responsive to NOX inhibitors and iron chelators.
  • Increased mitochondrial oxidant production, altered mitochondrial biogenesis, and impaired proteasome activity were found in RTT samples.
  • Activities of key antioxidant enzymes (glutathione peroxidase, superoxide dismutase, thioredoxin reductases) were significantly reduced in RTT.

Conclusions:

  • Systemic OS in RTT results from increased endogenous oxidants and impaired mitochondrial biogenesis.
  • Decreased antioxidant enzyme activity contributes to posttranslational protein modification and proteasome impairment in RTT.
  • These findings highlight the critical role of redox imbalance in RTT pathogenesis.
Keywords:
4HNEGlutathione peroxidaseNADPH oxidaseOxidative stressSuperoxide dismutase thioredoxin-reductases

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