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.

VPS35 regulates cell surface recycling and signaling of dopamine receptor D1

“…Multiple VPS35/retromer cargos have been identified so far, among which some are related to neuronal functions and neurodegenerative diseases, such as APP (Vieira, et al, 2010), BACE1 (Wen, et al, 2011), and AMPA receptors (Munsie, et al, 2015,Tian, et al, 2015). Herein, we found that overexpression of VPS35 could promote DRD1 recycling to cell surface, consequently leading to increased steady-state levels of cell surface DRD1.…”

“…Furthermore, VPS35 interacts genetically with another PD-associated gene EIF4G1 (Chartier-Harlin, et al, 2011); and they converge on α-synuclein pathology in PD (Dhungel, et al, 2015). Moreover, VPS35 can interact with AMPA receptor subunits and its deficiency or mutation impairs AMPA receptor trafficking and reduces dendritic spine maturation (Munsie, et al, 2015,Tian, et al, 2015). Nevertheless, how exactly VPS35 mutation or deficiency contributes to PD has yet to be fully determined.…”

A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration

“…Mutations in VPS35, VPS26A and the retromer accessory protein DNAJC13 [43][44][45][46] have been associated with late-onset autosomal dominant Parkinson's disease (PD) [47][48][49][50]. Indeed, the PD-linked VPS35(p.D620N) mutation displays a reduced ability to associate with the actin polymerizing WASH (Wiskott-Aldrich syndrome protein and SCAR Homology) complex [51][52][53] which leads to altered endosome-to-Golgi transport and autophagosome formation [54,44,55,56]. Perturbed function of the WASH complex is also implicated in hereditary spastic paraplegia [57].…”

Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

“…Characterization of the PD-causing Vps35 D620N mutation demonstrated that Vps35 D620N-retromer is unable to correctly traffic cargoes, such as CI-M6PR and post-synaptic AMPA receptors, the former of which results in improper processing and trafficking of cathepsin D (17,18). Moreover, previous reports suggest that the aforementioned sorting defect may arise from perturbed interactions with the WASH complex, a protein complex implicated in endosome-to-Golgi receptor sorting, and, consequently, may lead to a down-regu-lation of autophagy (19 -21).…”