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Hum Mol Genet. 2015 Mar 15;24(6):1691-703. doi: 10.1093/hmg/ddu582. Epub 2014 Nov 21.

Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson's disease VPS35 mutation p.D620N.

Author information

1
Department Medical Genetics, Centre for Applied Neurogenetics, Djavad Mowafagian Centre for Brain Health, Vancouver, Canada.
2
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.
3
Division of Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany.

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.

PMID:
25416282
DOI:
10.1093/hmg/ddu582
[Indexed for MEDLINE]

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