Faculty Collaboration Database

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. Am J Hum Genet 2016 Mar 03;98(3):500-513

Date

03/05/2016

Pubmed ID

26942284

Pubmed Central ID

PMC4800038

DOI

10.1016/j.ajhg.2016.01.014

Scopus ID

2-s2.0-84959881559 (requires institutional sign-in at Scopus site)   296 Citations

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.

Author List

Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M, Nicolas A, Cormier-Dequaire F, Hassoun SM, Pujol C, Ciura S, Erpapazoglou Z, Usenko T, Maurage CA, Sahbatou M, Liebau S, Ding J, Bilgic B, Emre M, Erginel-Unaltuna N, Guven G, Tison F, Tranchant C, Vidailhet M, Corvol JC, Krack P, Leutenegger AL, Nalls MA, Hernandez DG, Heutink P, Gibbs JR, Hardy J, Wood NW, Gasser T, Durr A, Deleuze JF, Tazir M, Destée A, Lohmann E, Kabashi E, Singleton A, Corti O, Brice A, French Parkinson's Disease Genetics Study (PDG), International Parkinson's Disease Genomics Consortium (IPDGC)

Author

Jing Dong PhD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Animals
COS Cells
Case-Control Studies
Consanguinity
Female
Gene Silencing
Genetic Heterogeneity
HEK293 Cells
Heterozygote
Homozygote
Humans
Male
Middle Aged
Parkinsonian Disorders
Pedigree
Phenotype
Protein Kinases
Proteins
Reproducibility of Results
Turkey
Ubiquitin-Protein Ligases