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

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.

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

“…The relevance of impaired mitochondrial quality control in the pathogenesis of PD is further corroborated by the recent identification of mutations in the VPS13C gene in the autosomal recessively inherited form of juvenile parkinsonism ( PARK23 ; OMIM: 616,840; Lesage et al 2016). We hypothesise that VPS13C could also have a role in organellar quality control of mitochondria.…”

“…Under physiological conditions, VPS13C was found to be localised in mitochondrial fractions and relocalises to the cytoplasm after mitochondrial damage in monkey and human cell lines (Lesage et al 2016). The PD-associated loss of VPS13C caused mitochondrial fragmentation, loss of membrane potential and increase PINK1/Parkin-mediated mitophagy after challenging cells with the mitochondrial uncoupler CCCP (carbonyl cyanide 3-chlorophenylhydrazone) (Lesage et al 2016). It has also been shown to colocalise with the lysosomal fraction in HeLa cells (Yang et al 2016).…”

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

“…Concerning the monogenic forms of PD were found mutations in 7 genes of AD transmission (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, HTRA2, TMEM230) and even more in those of AR transmission. Recent data provide evidence for new molecular pathways involving neurodevelopmental mechanisms [207,210], modulating the signaling processes at the endocytic pathway [142], synaptic vesicles endocytosis and trafficking in PD pathogenesis [202,206], maintaining the integrity of the cytoskeleton and axonal transport in neurons [192].…”

“…A hypothesis which has been advanced to explain the mitochondrial dysfunction when parkinsonian features were signaled in designer drug abusers [223] was the inhibitory effect of MPTP on mitochondrial complex 1 of the electron transporter chain [224], functionally linked with mitochondrial DNA mutations [225,226], sustained by the extrapyramidal phenotype induction in animal models by inhibitors of mitochondrial complex l [227]. VPS13C as a mitochondrial membrane protein interacts with PINK1 and Parkin in order to provide the mitochondrial morphology and membrane potential integrity [207]. Beside mitochondrial dysfunction, the impaired pathways involved in clearing abnormal cellular proteins and damaged organelles, the ubiquitin-proteasome system and the autophagic pathway involving lysosomal activity [30,228] play a crucial role in PD etiology.…”

“…VPS13C is a protein of mitochondrial membrane with role in maintaining of mitochondrial membrane potential and conformation [207].…”