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
(12)
,
Jean-François Deleuze
(18)
,
Meriem Tazir
(19)
,
Alain Destée
(20)
,
Ebba Lohmann
(8, 16)
,
Edor Kabashi
(1)
,
Andrew Singleton
(3)
,
Olga Corti
(1)
,
Alexis Brice
(1, 12)
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 U946 - 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 Commissariat à l'Energie Atomique Saclay
19 Service de Neurologie
20 Movement Disorders Unit
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 U946 - 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 Commissariat à l'Energie Atomique Saclay
19 Service de Neurologie
20 Movement Disorders Unit
Aude Nicolas
- Fonction : Auteur
- PersonId : 772390
- IdRef : 164777962
François Tison
- Fonction : Auteur
- PersonId : 938780
Marie Vidailhet
- Fonction : Auteur
- PersonId : 758783
- ORCID : 0000-0002-2409-9143
- IdRef : 074466208
Jean-Christophe Corvol
- Fonction : Auteur
- PersonId : 756631
- ORCID : 0000-0001-7325-0199
- IdRef : 087943492
Anne-Louise Leutenegger
- Fonction : Auteur
- PersonId : 175762
- IdHAL : anne-louise-leutenegger
- ORCID : 0000-0002-1302-4357
- IdRef : 077796780
Thomas Gasser
- Fonction : Auteur
- PersonId : 761300
- ORCID : 0000-0003-4882-2647
Alexandra Durr
- Fonction : Auteur
- PersonId : 758970
- ORCID : 0000-0002-8921-7104
- IdRef : 148675018
Edor Kabashi
- Fonction : Auteur
- PersonId : 774219
- ORCID : 0000-0003-4118-251X
Alexis Brice
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 862300
Connectez-vous pour contacter l'auteur
Résumé
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.
Domaines
Neurosciences [q-bio.NC]
Origine : Fichiers produits par l'(les) auteur(s)
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