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

• Published in: American journal of human genetics Vol. 98; no. 3; pp. 500 - 513
• Main Authors: Lesage, Suzanne, Deramecourt, Vincent, Jacoupy, Maxime, Hassoun, Sidi Mohamed, Pujol, Claire, Maurage, Claude-Alain, Sahbatou, Mourad, Liebau, Stefan, Bilgic, Basar, Emre, Murat, Erginel-Unaltuna, Nihan, Guven, Gamze, Tison, François, Tranchant, Christine, Corvol, Jean-Christophe, Krack, Paul, Hernandez, Dena G., Gibbs, J. Raphael, Hardy, John, Wood, Nicholas W., Durr, Alexandra, Deleuze, Jean-François, Tazir, Meriem, Destée, Alain, Lohmann, Ebba, Corti, Olga, Brice, Alexis, Vidailhet, Marie, Agid, Yves, Anheim, Mathieu, Bonnet, Anne-Marie, Borg, Michel, Broussolle, Emmanuel, Durif, Franck, Klebe, Stephan, Vérin, Marc, Viallet, François, Majounie, Elisa, Corvol, Jean Christophe, Ben-Shlomo, Yoav, Berg, Daniela, Bhatia, Kailash, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M., Brockmann, Kathrin, Burn, David J., Chen, Honglei, Clarke, Carl E., Cookson, Mark R., Counsell, Carl, van Dijk, Karin D., Dong, Jing, Escott-Price, Valentina, Evans, Jonathan R., Gray, Emma, Guerreiro, Rita, van Hilten, Jacobus J., Hollenbeck, Albert, Holmans, Peter, Hu, Michèle, Hudson, Gavin, Hunt, Sarah E., Kilarski, Laura L., Jansen, Iris E., Langford, Cordelia, Lees, Andrew, Lorenz, Delia, Lubbe, Steven, Lungu, Codrin, Martinez, María, Mätzler, Walter, McNeill, Alisdair, Moorby, Catriona, O’Sullivan, Sean S., Pearson, Justin, Ravina, Bernard, Rivadeneira, Fernando, Ryten, Mina, Schapira, Anthony, Sharma, Manu, Sheerin, Una-Marie, Sidransky, Ellen, Spencer, Chris C.A., Stefánsson, Kári, Strange, Amy, Talbot, Kevin, Trabzuni, Daniah, Uitterlinden, André G., van de Warrenburg, Bart, Williams-Gray, Caroline H., Winder-Rhodes, Sophie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2016; Elsevier (Cell Press); Elsevier
• Subjects: Adult; Aged; Animals; Case-Control Studies; Consanguinity; COS Cells; Female; Gene Silencing; Genetic Heterogeneity; HEK293 Cells; Heterozygote; Homozygote; Humans; Life Sciences; Male; Middle Aged; Mitophagy - genetics; Neurons and Cognition; Parkinsonian Disorders - diagnosis; Parkinsonian Disorders - genetics; Pedigree; Phenotype; Protein Kinases - genetics; Protein Kinases - metabolism; Proteins - genetics; Proteins - metabolism; Reproducibility of Results; Turkey; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Turkey
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2016.01.014

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.