title: Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration.
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 the human brain, VPS35 protein levels and distribution are similar in tissues from control and PD subjects, and VPS35 is not associated with Lewy body pathology. The common D620N missense mutation in VPS35 does not compromise its protein stability or localization to endosomal and lysosomal vesicles, or the vesicular sorting of the retromer cargo, sortilin, SorLA and cation-independent mannose 6-phosphate receptor, in rodent primary neurons or patient-derived human fibroblasts. 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 of human VPS35 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 dominant VPS35 mutations lead to neurodegeneration in PD consistent with a gain-of-function mechanism, and support a key role for VPS35 in the development of PD.
authors.affiliation: Laboratory of Molecular Neurodegenerative Research.
authors.forename: Elpida
authors.initials: E
authors.lastname: Tsika
authors.affiliation: Laboratory of Molecular Neurodegenerative Research.
authors.forename: Liliane
authors.initials: L
authors.lastname: Glauser
authors.affiliation: Laboratory of Molecular Neurodegenerative Research.
authors.forename: Roger
authors.initials: R
authors.lastname: Moser
authors.affiliation: Laboratory of Molecular Neurodegenerative Research.
authors.forename: Aris
authors.initials: A
authors.lastname: Fiser
authors.affiliation: Laboratory of Molecular Neurodegenerative Research.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Daniel
authors.affiliation: Department of Molecular Neuroscience.
authors.forename: Una-Marie
authors.initials: UM
authors.lastname: Sheerin
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Department of Molecular Neuroscience School of Pharmacy, University of Reading, Reading RG6 6AP, UK.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London WC1N 1PJ, UK.
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
authors.affiliation: Neurodegenerative Disease Laboratory, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Laboratory of Molecular Neurodegenerative Research Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA darren.moore@vai.org.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D000229:Dependovirus / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D055550:Protein Stability; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013312:Stress, Physiological; D022161:Transport Vesicles / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins
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