2. Academic Validation
  3. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

  • Am J Hum Genet. 2016 Mar 3;98(3):500-513. doi: 10.1016/j.ajhg.2016.01.014.
Suzanne Lesage 1,  Valérie Drouet 1,  Elisa Majounie 2,  Vincent Deramecourt 3,  Maxime Jacoupy 1,  Aude Nicolas 1,  Florence Cormier-Dequaire 4,  Sidi Mohamed Hassoun 1,  Claire Pujol 1,  Sorana Ciura 1,  Zoi Erpapazoglou 1,  Tatiana Usenko 1,  Claude-Alain Maurage 3,  Mourad Sahbatou 5,  Stefan Liebau 6,  Jinhui Ding 2,  Basar Bilgic 7,  Murat Emre 7,  Nihan Erginel-Unaltuna 8,  Gamze Guven 8,  François Tison 9,  Christine Tranchant 10,  Marie Vidailhet 11,  Jean-Christophe Corvol 4,  Paul Krack 12,  Anne-Louise Leutenegger 13,  Michael A Nalls 2,  Dena G Hernandez 2,  Peter Heutink 14,  J Raphael Gibbs 2,  John Hardy 15,  Nicholas W Wood 15,  Thomas Gasser 14,  Alexandra Durr 16,  Jean-François Deleuze 17,  Meriem Tazir 18,  Alain Destée 19,  Ebba Lohmann 20,  Edor Kabashi 1,  Andrew Singleton 2,  Olga Corti 21,  Alexis Brice 22,  French Parkinson's Disease Genetics Study (PDG),  International Parkinson's Disease Genomics Consortium (IPDGC)
Affiliations

Affiliations

  • 1 Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
  • 2 Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
  • 3 Department of Histology and Pathology, University of Lille Nord de France, Lille University Hospital, 59000 Lille, France.
  • 4 Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422, 75013 Paris, France.
  • 5 Fondation Jean Dausset-CEPH, 75010 Paris, France.
  • 6 Institute of Neuroanatomy, Eberhard Karls University Tübingen, 72074 Tübingen, Germany.
  • 7 Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34390 Istanbul, Turkey.
  • 8 Department of Genetics, Institute for Experimental Medicine, Istanbul University, 34390 Istanbul, Turkey.
  • 9 Institut des Maladies Neurodégénératives, Université de Bordeaux et CHU de Bordeaux, 33000 Bordeaux, France.
  • 10 Pôle Tête-Cou-CETD, Service de Neurologie, Hôpitaux Universitaires, 67000 Strasbourg, France.
  • 11 Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Pôle des Maladies du Système Nerveux, Fédération de Neurologie, Hôpital de la Salpêtrière, 75013 Paris, France.
  • 12 Neurology Department, CHU de Grenoble, Joseph Fourier University, and INSERM U836, 38000 Grenoble, France.
  • 13 Inserm U946, 75010 Paris, France; Université Paris Diderot, Institut Universitaire d'Hématologie, UMR946, 75010 Paris, France.
  • 14 Hertie Institute for Clinical Brain Research, University of Tübingen and DZNE, German Center for Neurodegenerative Diseases, 72074 Tübingen, Germany.
  • 15 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
  • 16 Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Department of Genetics and Cytogenetics, AP-HP, Hôpital de la Salpêtrière, 75013 Paris, France.
  • 17 Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, 91000 Evry, France.
  • 18 Service de Neurologie CHU Mustapha, 16000 Alger, Algérie.
  • 19 Movement Disorders Unit, Lille University, Inserm U837, Lille University Hospital, 59000 Lille, France.
  • 20 Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34390 Istanbul, Turkey; Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
  • 21 Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France. Electronic address: [email protected].
  • 22 Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Department of Genetics and Cytogenetics, AP-HP, Hôpital de la Salpêtrière, 75013 Paris, France. Electronic address: [email protected].
PMID: 26942284 DOI: 10.1016/j.ajhg.2016.01.014
Abstract

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent Mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

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