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

Suzanne Lesage 1, 2 Valérie Drouet 1, 2 Elisa Majounie 2, 3 Vincent Deramecourt 4 Maxime Jacoupy 1 Aude Nicolas 1 Florence Cormier-Dequaire 1, 5 Sidi mohamed Hassoun 1 Claire Pujol 1 Sorana Ciura 1 Zoi Erpapazoglou 1 Tatiana Usenko 1 Claude-Alain Maurage 4 Mourad Sahbatou 6 Stefan Liebau 7 Jinhui Ding 3 Basar Bilgic 8 Murat Emre 8 Nihan Erginel-Unaltuna 9 Gamze Guven 9 François Tison 10 Christine Tranchant 11 Marie Vidailhet 1, 12 Jean-Christophe Corvol 1, 5 Paul Krack 13 Anne-Louise Leutenegger 14, 15 Michael a. Nalls 3 Dena g. Hernandez 3 Peter Heutink 16 J. raphael Gibbs 3 John Hardy 17 Nicholas w. Wood 17 Thomas Gasser 16 Alexandra Durr 18 Jean-François Deleuze 19 Meriem Tazir 20 Alain Destée 21 Ebba Lohmann 8, 16 Edor Kabashi 1 Andrew Singleton 3 Olga Corti 1, * Alexis Brice 1, 18, *
* Corresponding author
1 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
2 Department of Neurodegenerative Diseases
3 Laboratory of Neurogenetics
4 Département d'histologie et de pathologie
5 CIC Neurosciences - Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière]
6 Fondation Jean Dausset CEPH
7 Institute of Neuroanatomy
8 Department of Neurology, Behavioural Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine
9 Department of Genetics
10 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
11 Pôle Tête-Cou-CETD
12 CHU Pitié-Salpêtrière [AP-HP]
13 Département de neurologie
14 Variabilité Génétique et Maladies Humaines
15 IUH - Institut Universitaire d'Hématologie
16 Hertie Institute for Clinical Brain Research [Tubingen]
17 Department of Molecular Neuroscience
18 Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière]
19 Commissariat à l'Energie Atomique Saclay
20 Service de Neurologie
21 Movement Disorders Unit
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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Suzanne Lesage, Valérie Drouet, Elisa Majounie, Vincent Deramecourt, Maxime Jacoupy, et al.. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. American Journal of Human Genetics, Elsevier (Cell Press), 2016, 98 (3), pp.500-513. ⟨10.1016/j.ajhg.2016.01.014⟩. ⟨hal-01289266⟩

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