VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology

Wen, Lei; Tang, Fu Lei; Hong, Yan; Luo, Shi Wen; Wang, C. L.; He, Wanxia; Shen, Chengyong; Jung, Ji-Ung; Xiong, Fei; Lee, Dae Hoon; Zhang, Quan Guang; Brann, Darrell W.; Kim, Tae Wan; Yan, Riqiang; Mei, Lin; Xiong, Wen Cheng

doi:10.1083/jcb.201105109

Cited by 231 publications

(210 citation statements)

References 73 publications

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“…SNX27 is part of the retromer complex, which has been previously implicated in adult neurodegenerative diseases. Decreased retromer expression is observed in patients with Alzheimer's disease (AD) [39][40][41], and this correlates with an increase in amyloidogenic processing of amyloid precursor protein (APP). There is also evidence suggestive of additional retromer accessory proteins as AD risk genes [42].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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The composition of the neuronal cell surface dictates synaptic plasticity and thereby cognitive development. This remodeling of the synapses is governed by the endocytic network which internalize transmembrane proteins, then sort them back to the cell surface or carry them to the lysosome for degradation. The multi-protein retromer complex is central to this selection, capturing specific transmembrane proteins and remodeling the cell membrane to form isolated cargo-enriched transport carriers. We investigated a consanguineous family with four patients who presented in infancy with intractable myoclonic epilepsy and lack of psychomotor development. Using exome analysis, we identified a homozygous deleterious mutation in SNX27, which encodes sorting nexin 27, a retromer cargo adaptor. In western analysis of patient fibroblasts, the encoded mutant protein was expressed at an undetectable level when compared with a control sample. The patients' presentation and clinical course recapitulate that reported for the SNX27 knock-out mouse. Since the cargo proteins for SNX27-mediated sorting include subunits of ionotropic glutamate receptors and endosome-to-cell surface synaptic insertion of AMPA receptors is severely perturbed in SNX27−/− neurons, it is proposed that at least part of the neurological aberrations observed in the patients is attributed to defective sorting of ionotropic glutamate receptors. SNX27 deficiency is now added to the growing list of neurodegenerative disorders associated with retromer dysfunction. * Peter J. Cullen: Pete.Cullen@bristol.ac.uk. * Orly Elpeleg: Elpeleg@Hadassah.org.il. Ethical standards statement.The experiments comply with the current laws of Israel.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…VPS35 is reduced in the hippocampus of late-onset AD patients (Small et al, 2005). VPps35-haploinsufficiency enhances AD-like neuropathology in the Tg2576 mouse model of AD (Wen et al, 2011). Suppressing VPS35 expression in neonatal hippocampal neurons results in “degenerative-like” morphology including abnormal dendritic spines and swollen axons (Wang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function

et al. 2015

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Vacuolar protein sorting-35 (VPS35) is a retromer component for endosomal trafficking. Mutations of VPS35 have been linked to familial Parkinson’s disease (PD). Here we showed that specific deletion of the VPS35 gene in DA neurons resulted in PD-like deficits including loss of DA neurons and accumulation of α-synuclein. Intriguingly, mitochondria became fragmented and mal-functional in VPS35-deficient DA neurons, phenotypes that could be restored by expressing VPS35 wild type, but not PD-linked mutant. Concomitantly, VPS35 deficiency or mutation increased mitochondrial E3 ubiquitin ligase-1 (MUL1) and thus led to mitofusin-2 (MFN2) degradation and mitochondrial fragmentation. Suppression of MUL1 expression ameliorated MFN2-reduction and DA neuron-loss, but not α-synuclein-accumulation. These results provide a cellular mechanism for VPS35-dysfunction in mitochondrial impairment and PD pathogenesis.

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“…The importance of SORL1 in particular has been confirmed by a recent large-scale genetic meta-analysis (Lambert et al, 2013). Further support for a pathogenic role has been provided by genetically modified retromer deficient animal models (Muhammad et al, 2008; Wen et al, 2011). It is within endosomes that APP is most likely to be cleaved by BACE1 (beta-site APP cleaving enzyme 1) (Small and Gandy, 2006), a β-secretase that initiates the ‘amyloidogenic’ processing of APP leading to the accumulation of the neurotoxic fragments β-CTF (β C-terminal fragment) and Aβ (amyloid β).…”

Section: Introductionmentioning

confidence: 99%

Isolating Pathogenic Mechanisms Embedded within the Hippocampal Circuit through Regional Vulnerability

Small

2014

Neuron

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Some of the most common and devastating disorders of the brain target the hippocampal formation. The hippocampal formation is a complex circuit of interconnected regions, and it is assumed that clues into the causes of these disorders are embedded within the circuit. Neuroimaging tools have been optimized to interrogate the malfunctioning hippocampal circuit, and by applying these tools to patients in the earliest stages of disease and to animal models, patterns of regional dysfunction have been established for Alzheimer’s disease, schizophrenia and cognitive aging. More recently, studies have begun deciphering the cellular and molecular reasons underlying regional dysfunction. Collectively, this information clarifies the pathophysiology of these disorders and informs on therapeutic strategies.

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VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology

Abstract: The retromer complex component VPS35 prevents activation of the BACE1 and Aβ production and thus plays an essential role in limiting Alzheimer’s disease neuropathology.

Cited by 231 publications

References 73 publications

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

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

VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function

Isolating Pathogenic Mechanisms Embedded within the Hippocampal Circuit through Regional Vulnerability

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