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Article

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

by
Yih-Ru Wu
1,†,
Chih-Hsin Lin
1,†,
Chih-Ying Chao
1,
Chia-Wen Chang
1,
Chiung-Mei Chen
1,* and
Guey-Jen Lee-Chen
2,*
1
Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, No. 5, Fusing St., Gueishan Township, Taoyuan County 33302, Taiwan
2
Department of Life Science, National Taiwan Normal University, 88 Ting-Chou Road, Section 4, Taipei 11677, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Brain Sci. 2020, 10(11), 783; https://doi.org/10.3390/brainsci10110783
Submission received: 25 September 2020 / Revised: 16 October 2020 / Accepted: 21 October 2020 / Published: 27 October 2020
(This article belongs to the Section Molecular and Cellular Neuroscience)
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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: Parkinson’s disease; VPS35; mutation screen; CI-MPR sorting; impaired mitochondrial morphology Parkinson’s disease; VPS35; mutation screen; CI-MPR sorting; impaired mitochondrial morphology
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MDPI and ACS Style

Wu, Y.-R.; Lin, C.-H.; Chao, C.-Y.; Chang, C.-W.; Chen, C.-M.; Lee-Chen, G.-J. Rare VPS35 A320V Variant in Taiwanese Parkinson’s Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology. Brain Sci. 2020, 10, 783. https://doi.org/10.3390/brainsci10110783

AMA Style

Wu Y-R, Lin C-H, Chao C-Y, Chang C-W, Chen C-M, Lee-Chen G-J. Rare VPS35 A320V Variant in Taiwanese Parkinson’s Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology. Brain Sciences. 2020; 10(11):783. https://doi.org/10.3390/brainsci10110783

Chicago/Turabian Style

Wu, Yih-Ru, Chih-Hsin Lin, Chih-Ying Chao, Chia-Wen Chang, Chiung-Mei Chen, and Guey-Jen Lee-Chen. 2020. "Rare VPS35 A320V Variant in Taiwanese Parkinson’s Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology" Brain Sciences 10, no. 11: 783. https://doi.org/10.3390/brainsci10110783

APA Style

Wu, Y.-R., Lin, C.-H., Chao, C.-Y., Chang, C.-W., Chen, C.-M., & Lee-Chen, G.-J. (2020). Rare VPS35 A320V Variant in Taiwanese Parkinson’s Disease Indicates Disrupted CI-MPR Sorting and Impaired Mitochondrial Morphology. Brain Sciences, 10(11), 783. https://doi.org/10.3390/brainsci10110783

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