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

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• Sequence variants in vacuolar protein sorting 35 (VPS35) are linked to Parkinson's disease (PD).
• Investigating the role of VPS35 genetic variants in Taiwanese PD patients is crucial.

Purpose of the Study:

• To identify and characterize genetic variants in VPS35 associated with Parkinson's disease in Taiwan.
• To elucidate the functional consequences of identified VPS35 mutations on cellular processes relevant to PD.

Main Methods:

• Sequencing of VPS35 cDNA in PD patients.
• Genotyping of identified mutations in a larger cohort of PD patients and controls.
• In vitro studies using 293T cells to assess the impact of VPS35 mutations on CI-MPR sorting and mitochondrial morphology.

Main Results:

• A novel heterozygous A320V mutation in VPS35 was identified in two late-onset PD patients and absent in controls.
• A320V mutant VPS35 expression increased VPS35-CI-MPR colocalization and decreased CI-MPR and LAMP2 levels.
• The mutation led to cathepsin D missorting, reduced alpha-synuclein proteolysis, increased MUL1, and MFN2 degradation, impacting mitochondrial morphology.

Conclusions:

• The VPS35 A320V mutation disrupts cation-independent mannose-6-phosphate receptor (CI-MPR) sorting.
• Impaired mitochondrial morphology and function are associated with the A320V mutation.
• These cellular disruptions may contribute to the pathogenesis of Parkinson's disease.