Beta Amyloid Peptide: Research Paper : Rare VPS35 A320V Variant in Taiwanese Parkinson's Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology

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 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.

Keywords: CI-MPR sorting; Parkinson's disease; VPS35; impaired mitochondrial morphology; mutation screen.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33120894/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.