Is the Oxidant/Antioxidant Status Altered in CADASIL Patients?

Jonica Campolo,Raffaella Valenti,Chiara Tomasello,Domenico Inzitari,Antonio Federico,Renata De Maria,Marina Frontali,Franco Taroni,Oberdan Parodi,Marina Parolini,Caterina Mariotti

doi:10.1371/journal.pone.0067077

Abstract

The altered aggregation of proteins in non-native conformation is associated with endoplasmic reticulum derangements, mitochondrial dysfunction and excessive production of reactive oxygen species. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary systemic vasculopathy, caused by NOTCH3 mutations within the receptor extracellular domain, that lead to abnormal accumulation of the mutated protein in the vascular wall. NOTCH3 misfolding could cause free radicals increase also in CADASIL. Aim of the study was to verify whether CADASIL patients have increased oxidative stress compared to unrelated healthy controls. We enrolled 15 CADASIL patients and 16 gender- and age-matched healthy controls with comparable cardiovascular risk factor. Blood and plasma reduced and total aminothiols (homocysteine, cysteine, glutathione, cysteinylglycine) were measured by HPLC and plasma 3-nitrotyrosine by ELISA. Only plasma reduced cysteine (Pr-Cys) and blood reduced glutathione (Br-GSH) concentrations differed between groups: in CADASIL patients Br-GSH levels were higher (p = 0.019) and Pr-Cys lower (p = 0.010) than in controls. No correlation was found between Br-GSH and Pr-Cys either in CADASIL patients (rho 0.25, P=0.36) or in controls (rho -0.15, P=0.44). Conversely, 3-nitrotyrosine values were similar in CADASIL and healthy subjects (p = 0.82). The high levels of antioxidant molecules and low levels of oxidant mediators found in our CADASIL population might either be expression of an effective protective action against free radical formation at an early stage of clinical symptoms or they could suggest that oxidative stress is not directly involved in the pathogenesis of CADASIL.

Highlights

Perturbation of the oxidant/antioxidant balance within the cells has been suggested to be involved in the pathogenesis of several neurodegenerative disorders such as stroke [1], Parkinson’s disease [2] and Alzheimer’s disease [3]
The altered aggregation of proteins in non-native conformation is generally associated with derangements of the endoplasmic reticulum and stress, which leads to mitochondrial dysfunction and excessive production of reactive oxygen species (ROS) [4]
CADASIL population Among the 15 enrolled CADASIL patients, a history of migraine was present in 4 subjects (27%), 3 of whom (20%) showed no other clinical manifestation

Summary

Introduction

Perturbation of the oxidant/antioxidant balance within the cells has been suggested to be involved in the pathogenesis of several neurodegenerative disorders such as stroke [1], Parkinson’s disease [2] and Alzheimer’s disease [3]. These neurological disorders are associated with the production of abnormally aggregated proteins and belong to the group of protein conformational diseases. The altered aggregation of proteins in non-native conformation is generally associated with derangements of the endoplasmic reticulum and stress, which leads to mitochondrial dysfunction and excessive production of reactive oxygen species (ROS) [4]. Peroxynitrite is a powerful oxidant and can nitrate aromatic amino acid residues such as tyrosine to form nitrotyrosine

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