VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation.

Yun Tian,Bei-Sha Tang,Wen-Cheng Xiong,Xiangdong Sun,Lei Wen,Lin Mei,Fu-Lei Tang

doi:10.1186/s13041-015-0156-4

Abstract

BackgroundVacuolar protein sorting 35 (VPS35), a key component of retromer, plays an important role in endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is a risk factor for neurodegenerative disorders, including AD (Alzheimer’s disease) and PD (Parkinson’s disease). However, exactly how VPS35-deficiency contributes to AD or PD pathogenesis remains poorly understood.ResultsWe found that VPS35-deficiency impaired dendritic spine maturation and decreased glutamatergic transmission. AMPA receptors, GluA1 and GluA2, are significantly reduced in purified synaptosomal and PSD fractions from VPS35-deficient brain. The surface levels of AMPA receptors are also decreased in VPS35-deficient neurons. Additionally, VPS35 interacted with AMPA-type receptors, GluA1 and GluA2. Overexpression of GluA2, but not GluA1, could partially restore the spine maturation deficit in VPS35-deficient neurons.ConclusionsThese results provide evidence for VPS35’s function in promoting spine maturation, which is likely through increasing AMPA receptor targeting to the postsynaptic membrane. Perturbation of such a VPS35/retromer function may contribute to the impaired glutamatergic transmission and pathogenesis of neurodegenerative disorders, such as AD and PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0156-4) contains supplementary material, which is available to authorized users.

Highlights

Vacuolar protein sorting 35 (VPS35), a key component of retromer, plays an important role in endosometo-Golgi retrieval of membrane proteins
Tian et al Molecular Brain (2015) 8:70 and selective deletion of VPS35 in dopamine neurons, we have demonstrated that loss of VPS35 function in dopamine neurons results in Parkinson’s disease (PD)-relevant neuropathology [15, 16]
Our results suggest that VPS35 plays a crucial role in regulating AMPA receptor trafficking, which may underlie its function in promoting spine maturation and glutamatergic neurotransmission, revealing a molecular mechanisms by which VPS35/retromer in hippocampal neurons prevents Alzheimer’s disease (AD)-neuro-pathogenesis

Summary

Introduction

Vacuolar protein sorting 35 (VPS35), a key component of retromer, plays an important role in endosometo-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is a risk factor for neurodegenerative disorders, including AD (Alzheimer’s disease) and PD (Parkinson’s disease). In the early stage of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), synaptic neurotransmission is often defective. This synaptic deficit appears to be an earlier deficit than neuron-loss [1,2,3]. It is of considerably interest to investigate how synapses are altered in the course of neurodegenerative disorders. Vacuolar protein sorting-35 (VPS35) is an important component of the cargo-recognition retromer complex

Methods

Results

Conclusion