2. Academic Validation
  3. Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration

Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration

  • Brain. 2016 Feb;139(Pt 2):346-54. doi: 10.1093/brain/awv350.
Eliska Holzerova 1,  Katharina Danhauser 2,  Tobias B Haack 1,  Laura S Kremer 1,  Marlen Melcher 2,  Irina Ingold 3,  Sho Kobayashi 4,  Caterina Terrile 5,  Petra Wolf 5,  Jörg Schaper 6,  Ertan Mayatepek 2,  Fabian Baertling 2,  José Pedro Friedmann Angeli 3,  Marcus Conrad 3,  Tim M Strom 5,  Thomas Meitinger 7,  Holger Prokisch 8,  Felix Distelmaier 9
Affiliations

Affiliations

  • 1 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
  • 2 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
  • 3 4 Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
  • 4 4 Institute of Developmental Genetics, Helmholtz Zentrum München, Ingolstädter 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.
  • 5 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
  • 6 6 Medical Faculty, Department of Diagnostic and Interventional Radiology, University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
  • 7 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany 7 Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
  • 8 1 Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675 Munich, Germany 2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany [email protected] [email protected].
  • 9 3 Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany [email protected] [email protected].
PMID: 26626369 DOI: 10.1093/brain/awv350
Abstract

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 dysfunction. 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 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.

Keywords

ROS; idebenone; mitochondria; neurodegeneration; thioredoxin.

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