2. Academic Validation
  3. Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia

Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia

  • Brain. 2021 Jun 22;144(5):1467-1481. doi: 10.1093/brain/awab071.
Adriana P Rebelo 1,  Ilse Eidhof 2,  Vivian P Cintra 1,  Léna Guillot-Noel 3 4,  Claudia V Pereira 5,  Dagmar Timmann 6,  Andreas Traschütz 7 8,  Ludger Schöls 7 8,  Giulia Coarelli 3,  Alexandra Durr 3 9,  Mathieu Anheim 10 11,  Christine Tranchant 10 11,  Bart van de Warrenburg 12,  Claire Guissart 13,  Michel Koenig 13,  Jack Howell 1,  Carlos T Moraes 5,  Annette Schenck 2,  Giovanni Stevanin 3 4,  Stephan Züchner 1,  Matthis Synofzik 7 8,  PREPARE network
Affiliations

Affiliations

  • 1 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
  • 2 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 3 Sorbonne Université, Paris Brain Institute, AP-HP, INSERM, CNRS, Pitié-Salpêtrière University Hospital, Paris, France.
  • 4 Neurogenetics Team, EPHE, PSL University, Paris, France.
  • 5 Departments of Neurology and Cell Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 6 Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.
  • 7 Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 8 German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
  • 9 Department of genetics, Hôpital de La Pitié-Salpétrière, Paris, France.
  • 10 Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • 11 Institute of Genetics and Molecular and Cellular Biology, INSERM-U964/CNRS-UMR7104, University of Strasbourg, Illkirch, France.
  • 12 Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
  • 13 EA7402 Institut Universitaire de Recherche Clinique and Laboratoire de Génétique Moléculaire, CHU and Université de Montpellier, Montpellier, France.
PMID: 33889951 DOI: 10.1093/brain/awab071
Abstract

Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of Reactive Oxygen Species. Excessive levels of Reactive Oxygen Species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately Apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased Glutathione Peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to Apoptosis triggered by Reactive Oxygen Species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.

Keywords

PRDX3; ROS; ataxia.

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