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Human Thioredoxin 2 Deficiency Impairs Mitochondrial Redox

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Human Thioredoxin 2 Deficiency Impairs Mitochondrial Redox doi:10.1093/brain/awv350 BRAIN 2016: 139; 346–354 | 346 REPORT Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration Eliska Holzerova,1,2 Katharina Danhauser,3 Tobias B. Haack,1,2 Laura S. Kremer,1,2 Marlen Melcher,3 Irina Ingold,4 Sho Kobayashi,4,5 Caterina Terrile,2 Petra Wolf,2 Jo¨rg Schaper,6 Ertan Mayatepek,3 Fabian Baertling,3 Jose´ Pedro Friedmann Angeli,4 Marcus Conrad,4 Tim M. Strom,2 Thomas Meitinger1,2,7 Holger Prokisch1,2,* and Downloaded from Felix Distelmaier3,* *These authors contributed equally to this work. http://brain.oxfordjournals.org/ Thioredoxin 2 (TXN2; also known as Trx2) is a small mitochondrial redox protein essential for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Exome sequencing in a 16-year-old adolescent suffering from an infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy, uncovered a homozygous stop mutation in TXN2. Analysis of patient-derived fibroblasts demonstrated absence of TXN2 protein, increased reactive oxygen species levels, impaired oxidative stress defence and oxidative phosphorylation dysfunc- tion. Reconstitution of TXN2 expression restored all these parameters, indicating the causal role of TXN2 mutation in disease development. Supplementation with antioxidants effectively suppressed cellular reactive oxygen species production, improved cell by guest on March 10, 2016 viability and mitigated clinical symptoms during short-term follow-up. In conclusion, our report on a patient with TXN2 deficiency suggests an important role of reactive oxygen species homeostasis for human neuronal maintenance and energy metabolism. 1 Institute of Human Genetics, Technische Universita¨tMu¨ nchen, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum Mu¨ nchen, Ingolsta¨dter Landstr. 1, 85764 Neuherberg, Germany 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children’s Hospital, Heinrich-Heine-University Du¨ sseldorf, Moorenstr. 5, 40225 Du¨ sseldorf, Germany 4 Institute of Developmental Genetics, Helmholtz Zentrum Mu¨ nchen, Ingolsta¨dter Landstr. 1, 85764 Neuherberg, Germany 5 Division of Animal Production, Specialty of Bioproduction Science, The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate 020-8550, Japan 6 Medical Faculty, Department of Diagnostic and Interventional Radiology, University Du¨ sseldorf, Moorenstr. 5, 40225 Du¨ sseldorf, Germany 7 Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany Correspondence to: Holger Prokisch, Institute of Human Genetics, Technische Universita¨tMu¨ nchen, Trogerstr. 32, 81675 Munich, Germany E-mail: [email protected] Received May 21, 2015. Revised August 18, 2015. Accepted October 15, 2015. Advance Access publication December 1, 2015 ß The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected] TXN2 mutations cause neurodegeneration BRAIN 2016: 139; 346–354 | 347 Correspondence may also be addressed to: Felix Distelmaier, Department of General Paediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Du¨ sseldorf, Germany E-mail: [email protected] Keywords: idebenone; mitochondria; neurodegeneration; ROS; thioredoxin 0 0 Abbreviation: CM-H2DCFA = 5-(and-6)-chloromethyl-2 ,7 -dichlorodihydrofluorescein diacetate; GSH = glutathione; OXPHOS = oxidative phosphorylation system; ROS = reactive oxygen species Introduction 2007). The mitochondrial TXN system is composed of TXN2, thioredoxin reductase 2 (TXNRD2), peroxiredoxin The umbrella term reactive oxygen species (ROS) comprises 3 (PRDX3) and peroxiredoxin 5 (PRDX5) (Lu and a wide array of partially reduced forms of oxygen, which Holmgren, 2012; Mahmood et al., 2013). TXN2 is ubiqui- are common by-products of cellular metabolism. Most tously expressed with highest expression levels in the brain intracellular ROS are derived from mitochondrial super- (Rybnikova et al., 2000). It is encoded by a nuclear gene, Downloaded from oxide, which results from the monoelectronic reduction of TXN2, containing a mitochondrial targeting sequence. oxygen (Zorov et al., 2014; Holzerova and Prokisch, Along with TXNRD2 and PRDX3/5, TXN2 is responsible 2015). Superoxide is efficiently dismutated to hydrogen for eliminating H2O2, thus maintaining a reducing mito- peroxide (H2O2) via superoxide dismutase, consequently chondrial matrix environment (Lu and Holmgren, 2012). making the mitochondria a major site for H2O2 generation. Moreover, TXN2 is involved in controlling the intrinsic- http://brain.oxfordjournals.org/ In this context, tight regulation of mitochondrial H2O2 mitochondrial apoptotic pathway (Tanaka et al., 2002; levels is critical for their ability to participate in physio- Lu and Holmgren, 2012). Animal studies suggest that logical cell signalling and to avoid non-specific oxidative TXN2 is essential for prenatal development as total ab- damage (Sena and Chandel, 2012). Therefore, an efficient sence of TXN2 in a mouse knockout model causes exence- enzymatic machinery to buffer H2O2 levels has developed phaly and embryonic lethality (Nonn et al., 2003). within the mitochondrial matrix (Fig. 1). Key proteins In this study, we describe a 16-year-old adolescent suf- involved in these processes are members of the thioredoxin fering from early-onset neurodegeneration and severe cere- (TXN) and the glutathione (GSH) systems (Zhang et al., bellar atrophy associated with a homozygous stop mutation by guest on March 10, 2016 Figure 1 Function of TXN2 in the ROS defence system. The schematic representation of the ROS scavenging systems shows involved proteins in two crosslinked pathways within the mitochondrial matrix. Different proteins as well as complexes of the oxidative phosphorylation À system (OXPHOS) produce reactive oxygen species in the form of superoxide (O2 ), which spontaneously converts to hydrogen peroxide (H2O2), or with the help of manganese superoxide dismutase (MnSOD). Within mitochondria, H2O2 is sensed by PRDX3 and oxidation of PRDX3 is reduced by TXN2, which is highlighted in red due to a missing function. TXN2 is reduced by TXNRD2 and NAPDH. In the glutathione pathway, glutathione peroxidase (GPx) reduces H2O2 and is subsequently reduced by GSH molecules, which form dimers (GSSG) or by glutaredoxin 2 (GLRX2). Using NADPH, glutathione reductase (GSR) reduces dimers of GSH. Inhibitors of the systems are depicted in red. DNCB = 2,4-dinitrochlorobenzene; IMM = inner mitochondrial membrane. 348 | BRAIN 2016: 139; 346–354 E. Holzerova et al. in TXN2. This mutation causes impaired ROS homeostasis and secondary mitochondrial dysfunction. Material and methods Sequencing A DNA sample from the patient was sequenced by Whole Case report Exome Sequencing using SureSelect Human All Exon The boy is the first child of healthy, non-consanguineous 50 Mb V5 Kit (Agilent) on a HiSeq2500 system German parents. Prenatal ultrasound at 16 weeks gestation (Illumina) (Haack et al., 2012; Kornblum et al., 2013). revealed bilateral subependymal cysts and brachycephaly The mutation was confirmed by Sanger sequencing in the but was otherwise normal. Chorion biopsy and foetal patient’s and parents’ samples. chromosome analysis were performed and revealed no abnormalities. The child was born at term without compli- Drug sensitivity assay and antioxidant cations. Apart from primary microcephaly, no specific dys- treatment morphic features or anomalies were seen. However, the parents noted that the child appeared relatively quiet and Human fibroblasts were cultured overnight on 96-well less active. plate in Dulbecco’s modified Eagle medium (DMEM), At the age of 6 months, he was severely microcephalic 10% foetal bovine serum, 1% penicillin-streptomycin, m Æ Downloaded from (head circumference 4 cm below third percentile) and 200 M uridine, antioxidants when indicated. On the following day, the cells were exposed to increasing concen- showed reduced spontaneous movements. Brain MRI de- trations of the indicated compounds dissolved in DMEM. tected an abnormally increased T signal intensity of the 2 Cell viability was determined by AquaBluer Kit cerebellum and indicated global brain atrophy. In addition, (MultiTarget Pharmaceuticals LLC) after 72 h of abnormal hippocampal shape and bilateral subependymal http://brain.oxfordjournals.org/ cultivation. cysts were seen (Fig. 2A–F). Lumbar puncture and analysis of CSF revealed elevated lactate (4.6 mmol/l, norm 52.8 mmol/l) and protein (67 mg/dl; norm 550 mg/ Lentiviral gene rescue dl) levels. In addition, blood lactate was moderately The wild-type sequence of the TXN2 gene was amplified increased (up to 3.1 mmol/l, norm 51.6 mmol/l). from a control cDNA and cloned into pLenti6.3/V5- Õ Õ Follow-up at the age of 14 months revealed impaired TOPO TA Cloning Kit (Invitrogen) for expression of psychomotor development characterized by markedly dis- TXN2 in human fibroblasts (Kornblum et al., 2013). turbed muscle tone and movement coordination. Brain by guest on March 10, 2016 MRI demonstrated a rapid progression of cerebellar atro- SDS PAGE and western blot analysis phy and indicated delayed myelination. At the age of 22 months, a muscle biopsy with biochemical analysis of the Protein lysates were separated by sodium dodecyl sulphate oxidative
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