Abstract
Sequence variants in vacuolar protein sorting 35 (VPS35) have been reported to be associated with Parkinson’s disease (PD). To investigate if the genetic variants in VPS35 contribute to Taiwanese PD, VPS35 cDNA fragments from 62 patients with PD were sequenced. A cohort of PD (n = 560) and ethnically matched controls (n = 506) were further examined for the identified mutation. The effects of the mutation on cation-independent mannose-6-phosphate receptor (CI-MPR) sorting and mitochondrial morphology were further examined in 293T cells expressing the mutant VPS35. Here, a novel heterozygous A320V in the VPS35 gene was identified in two late-onset PD (LOPD) patients, which was absent in 506 normal controls. Expression of the A320V mutant in 293T cells demonstrated increased colocalization of VPS35 with CI-MPR and decreased CI-MPR and lysosomal-associated membrane protein 2 (LAMP2) levels. Decreased CI-MPR manifested in missorting of cathepsin D and decreased proteolysis of α-synuclein. A320V mutation also increased mitochondrial E3 ubiquitin protein ligase 1 (MUL1) and thus led to mitofusin 2 (MFN2) degradation. The results suggest that the expression of VPS35 A320V leads to disrupted CI-MPR sorting and impaired mitochondrial morphology, which may partly explain its action in PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease, and its pathogenesis is still unknown
A320V was found in another late-onset PD (LOPD) patient (H1967) upon PCR 5and
mitofusin 2 (MFN2), we examined whether vacuolar protein sorting 35 (VPS35) A320V mutant
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease, and its pathogenesis is still unknown. A complex interaction between genetic and environmental factors contributes to development of this disease [1]. Genetic research in PD has identified mutations in several genes, including SNCA, LRRK2, and VPS35 or PARKIN, PINK1, DJ-1, ATP13A2, PLA2G6, and FBXO7, which are inherited in an autosomal dominant or autosomal recessive manner, respectively [2]. Common genetic variations at the SNCA, LRRK2, and GBA loci confer risk for developing idiopathic PD [2]. Reported genes are DNAJC13, CHCHD2, and TMEM230 for dominant PD and SYNJ1, RAB39B DNAJC6, VPS13C, and PTRHD1 for recessive PD [3]. The pathogenicity of some newly reported genes (DNAJC13, CHCHD2, and TMEM230) remains to
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