Dataset Information

Rare VPS35 A320V Variant in Taiwanese Parkinson's Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology.

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 ?-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.

SUBMITTER: Wu YR

PROVIDER: S-EPMC7692537 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rare VPS35 A320V Variant in Taiwanese Parkinson's Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology.

Wu Yih-Ru YR Lin Chih-Hsin CH Chao Chih-Ying CY Chang Chia-Wen CW Chen Chiung-Mei CM Lee-Chen Guey-Jen GJ

Brain sciences 20201027 11

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-MP ...[more]

PMID: 33120894

Similar Datasets

Project description:Recently, we reported that increased expression of CASP9 pro-domain, at the endosomal membrane in response to HSP90 inhibition, mediates a cell-protective effect that does not involve CASP9 apoptotic activity. We report here that a non-apoptotic activity of endosomal membrane CASP9 facilitates the retrograde transport of IGF2R/CI-MPR from the endosomes to the trans-Golgi network, indicating the involvement of CASP9 in endosomal sorting and lysosomal biogenesis. CASP9-deficient cells demonstrate the missorting of CTSD (cathepsin D) and other acid hydrolases, accumulation of late endosomes, and reduced degradation of bafilomycin A1-sensitive proteins. In the absence of CASP9, IGF2R undergoes significant degradation, and its rescue is achieved by the re-expression of a non-catalytic CASP9 mutant. This endosomal activity of CASP9 is potentially mediated by herein newly identified interactions of CASP9 with the components of the endosomal membrane transport complexes. These endosomal complexes include the retromer VPS35 and the SNX dimers, SNX1-SNX5 and SNX2-SNX6, which are involved in the IGF2R retrieval mechanism. Additionally, CASP9 interacts with HGS/HRS/ESCRT-0 and the CLTC (clathrin heavy chain) that participate in the initiation of the endosomal ESCRT degradation pathway. We propose that endosomal CASP9 inhibits the endosomal membrane degradative subdomain(s) from initiating the ESCRT-mediated degradation of IGF2R, allowing its retrieval to transport-designated endosomal membrane subdomain(s). These findings are the first to identify a cell survival, non-apoptotic function for CASP9 at the endosomal membrane, a site distinctly removed from the cytoplasmic apoptosome. Via its non-apoptotic endosomal function, CASP9 impacts the retrograde transport of IGF2R and, consequently, lysosomal biogenesis.Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; BafA1: bafilomycin A1; CASP: caspase; CLTC/CHC: clathrin, heavy chain; CTSD: cathepsin D; ESCRT: endosomal sorting complexes required for transport; HEXB: hexosaminidase subunit beta; HGS/HRS/ESCRT-0: hepatocyte growth factor-regulated tyrosine kinase substrate; IGF2R/CI-MPR: insulin like growth factor 2 receptor; ILV: intraluminal vesicles; KD: knockdown; KO: knockout; M6PR/CD-MPR: mannose-6-phosphate receptor, cation dependent; MEF: murine embryonic fibroblasts; MWU: Mann-Whitney U test; PepA: pepstatin A; RAB7A: RAB7, member RAS oncogene family; SNX-BAR: sorting nexin dimers with a Bin/Amphiphysin/Rvs (BAR) domain each; TGN: trans-Golgi network; TUBB: tubulin beta; VPS26: VPS26 retromer complex component; VPS29: VPS29 retromer complex component; VPS35: VPS35 retromer complex component.

Dataset Information

Rare VPS35 A320V Variant in Taiwanese Parkinson's Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology.

Publications

Rare <i>VPS35</i> A320V Variant in Taiwanese Parkinson's Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets