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

Sequence variants in vacuolar protein sorting 35 () have been reported to be associated with Parkinson's disease (PD). To investigate if the genetic variants in contribute to Taiwanese PD, cDNA fragments from 62 patients with PD were sequenced. A cohort of PD ( = 560) and ethnically matched controls ( = 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 . Here, a novel heterozygous A320V in the 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 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 A320V leads to disrupted CI-MPR sorting and impaired mitochondrial morphology, which may partly explain its action in PD.