Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration

Elpida Tsika, Liliane Glauser, Roger Moser, Aris Fiser, Guillaume Daniel, Una Marie Sheerin, Andrew Lees, Juan C. Troncoso, Patrick A. Lewis, Rina Bandopadhyay, Bernard L. Schneider, Darren J. Moore

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the vacuolar protein sorting 35 homolog (VPS35) gene at the PARK17 locus, encoding a key component of the retromer complex, were recently identified as a new cause of late-onset, autosomal dominant Parkinson's disease (PD). Here we explore the pathogenic consequences of PD-associated mutations in VPS35 using a number of model systems. VPS35 exhibits a broad neuronal distribution throughout the rodent brain, including within the nigrostriatal dopaminergic pathway. In thehumanbrain,VPS35protein levelsanddistribution are similar in tissues from control and PD subjects, and VPS35 is not associated with Lewy body pathology. ThecommonD620Nmissensemutation inVPS35does notcompromise its protein stability or localization to endosomal and lysosomal vesicles, or the vesicular sorting of the retromer cargo, sortilin, SorLA and cationindependentmannose6-phosphate receptor, in rodent primaryneurons or patient-derivedhumanfibroblasts. In yeast we show that PD-linked VPS35 mutations are functional and can normally complement VPS35 null phenotypes suggesting that they do not result in a loss-of-function. In rat primary cortical cultures the overexpression ofhumanVPS35 induces neuronal cell death and increases neuronal vulnerability to PD-relevant cellular stress. In a novel viral-mediated gene transfer rat model, the expression of D620N VPS35 induces the marked degeneration of substantia nigra dopaminergic neurons and axonal pathology, a cardinal pathological hallmark of PD. Collectively, these studies establish that dominantVPS35mutations lead toneurodegeneration inPDconsistent with a gain-of-function mechanism, and support a key role for VPS35 in the development of PD.

Original languageEnglish (US)
Article numberddu178
Pages (from-to)4621-4638
Number of pages18
JournalHuman molecular genetics
Volume23
Issue number17
DOIs
StatePublished - Sep 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration'. Together they form a unique fingerprint.

Cite this