title: Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N.
abstract: Vacuolar protein sorting 35 (VPS35) is a core component of the retromer complex, crucial to endosomal protein sorting and intracellular trafficking. We recently linked a mutation in VPS35 (p.D620N) to familial parkinsonism. Here, we characterize human VPS35 and retromer function in mature murine neuronal cultures and investigate neuron-specific consequences of the p.D620N mutation. We find VPS35 localizes to dendritic spines and is involved in the trafficking of excitatory AMPA-type glutamate receptors (AMPARs). Fundamental neuronal processes, including excitatory synaptic transmission, AMPAR surface expression and synaptic recycling are altered by VPS35 overexpression. VPS35 p.D620N acts as a loss-of-function mutation with respect to VPS35 activity regulating synaptic transmission and AMPAR recycling in mouse cortical neurons and dopamine neuron-like cells produced from induced pluripotent stem cells of human p.D620N carriers. Such perturbations to synaptic function likely produce chronic pathophysiological stress upon neuronal circuits that may contribute to neurodegeneration in this, and other, forms of parkinsonism.
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: L N
authors.initials: LN
authors.lastname: Munsie
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada, Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 2B5 amilnerwood@can.ubc.ca amilnerwood@gmail.com.
authors.forename: A J
authors.initials: AJ
authors.lastname: Milnerwood
authors.affiliation: Division of Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Seibler
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: D A
authors.initials: DA
authors.lastname: Beccano-Kelly
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Tatarnikov
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Khinda
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Volta
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Kadgien
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: L P
authors.initials: LP
authors.lastname: Cao
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Tapia
authors.affiliation: Division of Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics*; D021381:Protein Transport; D017470:Receptors, Glutamate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D017470:Receptors, Glutamate; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins