Blood metal levels and related antioxidant enzyme activities in patients with ataxia telangiectasia

NEUROBIOLOGY OF DISEASE

卷:81

Article

Squadrone, Stefania¹  Brizio, Paola¹  Mancini, Cecilia²  Pozzi, Elisa²  Cavalieri, Simona^2,3  Abete, Maria Cesarina¹  Brusco, Alfredo^2,3 

[1] Ist Zooprofilatt Sperimentale Piemonte Liguria &, I-10154 Turin, Italy

[2] Univ Turin, Dept Med Sci, I-10126 Turin, Italy

[3] Citta Salute & Sci Univ Hosp, Med Genet Unit, I-10126 Turin, Italy

关键词: Ataxia telangiectasia;    Metals;    Biomarker;    Essential trace elements;    Cu;    Zn;    SOD;    Catalase;   

DOI  :  10.1016/j.nbd.2015.04.001

来源: Elsevier

【 摘 要 】

Transition metals are cofactors for a wide range of vital enzymes and are directly or indirectly involved in the response against reactive oxygen species (ROS), which can damage cellular components. Their altered homeostasis has been studied in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), but no data are available on rarer conditions. We aimed at studying the role of essential trace elements in ataxia telangiectasia (AT), a rare form of pediatric autosomal recessive cerebellar ataxia with altered antioxidant response. We found an increased level of copper (Cu, p = 0.0002) and a reduced level of zinc (Zn, p = 0.0002) in the blood of patients (n. 16) compared to controls, using inductively coupled plasma mass spectrometry (ICP-MS). Other trace elements involved in the oxidative stress response, such as manganese (Mn) and selenium (Se), were unaltered. Cu/Zn-dependent superoxide dismutase (SOD1) was shown to have a 30% reduction in gene expression and 40% reduction in enzyme activity upon analysis of lymphoblastoid cell lines of patients (Student's t-test, p = 0.0075). We also found a 30% reduction of Mn-SOD (SOD2; Student's t-test, p = 0.02), probably due to a feedback regulatory loop between the two enzymes. The expression of antioxidant enzymes, such as erythrocyte glutathione peroxidase (GPX1), and SOD2 was unaltered, whereas catalase (CAT) was increakd in A-T cells, both at the mRNA level and in terms of enzyme activity (similar to 25%). Enhanced CAT expression can be attributed to the high ROS status, which induces CAT transcription. These results suggest that alterations in essential trace elements and their related enzymes may play a role in the pathogenesis of A-T, although we cannot conclude if altered homeostasis is a direct effect of A-T mutated genes (ATM). Altered homeostasis of trace elements may be more prevalent in neurodegenerative diseases than previously thought, and it may represent both a biomarker and a generic therapeutic target for different disorders with the common theme of altered antioxidant enzyme responses associated with an unbalance of metals. (C) 2015 Elsevier Inc. All rights reserved.

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