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, ) Parkin regulates mitochondrial HSD17B10 levels G Bertolin et al ARTICLE Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy
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10 Murat Emre, 10 Nihan Erginel-Unaltuna, 11 Gamze Guven, 11 François Tison, p.12 ,
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, 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, 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)
, expressed as the proportion of COS-7 cells without PMPCB (black bars) or TOMM20 (gray bars) staining; the siVPS13C treatment increased and siPINK1 decreased the proportion. In the absence of exogenous Parkin ($Parkin; cells overproducing the control protein EGFP) or CCCP (not shown), all the cells harbored normal mitochondrial PMPCB staining, whether or not VPS13C was silenced (means 5 SEM, B) Quantification of mitophagy in the conditions described in (A)
, nM) of each siRNA and 48 hr of CCCP treatment. The mitophagy-promoting effect of VPS13C depletion was abolished by concomitant silencing of PINK1 (means 5 SEM, C) Proportion of COS-7 cells without PMPCB staining after transfection with half-doses
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, Supplemental Information Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy
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