Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation

McGough, Ian J.; Steinberg, Florian; Jia, Da; Barbuti, Peter A.; McMillan, Kirsty J; Heesom, Kate J; Whone, Alan; Caldwell, Maeve A.; Billadeau, Daniel D.; Rosen, Michael K.; Cullen, Peter J.

doi:10.1016/j.cub.2014.07.004

Cited by 43 publications

(49 citation statements)

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“…Similar trafficking defects on CI-M6PR have been reported in cell-based models expressing PD-causing retromer variant Vps35 D620N. This variant is assembled into the retromer complex correctly, however, the presence of Vps35 D620N alters the intracellular distribution of CI-M6PR and leads to an elevation of procathepsin D in various cell types including fibroblast cells isolated from PD patients carrying Vps35 D620N variant [76,85,86]. Recent work reported an additional variant, Vps35 R524W, is also associated with the sorting defects of CI-M6PR.…”

Section: Impaired Endolysosomal-mediated Protein Degradationsupporting

confidence: 67%

The functional roles of retromer in Parkinson's disease

2017

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The endosomal system is critical for the maintenance of intracellular homeostasis, and defects in this system are often linked to neurological disorders. The retromer complex is a critical coordinator of endosomal dynamics and has functional roles in multiple cellular processes through sorting cargoes from endosomes to the trans-Golgi network (TGN) or to the plasma membrane. Mammalian retromer comprises a core Vps26-Vps35-Vps29 trimer and associates with a range of proteins to generate endosomal tubular-vesicular carriers. Alterations in retromer function or its molecular organization have been a rising risk factor for Parkinson's disease (PD). Although genetic evidence has shown several variants within retromer in late-onset PD cases, the exact molecular machineries by which retromer variants induce the development of PD are still not completely elucidated. In this Review, we will focus on the functional roles of retromer in neuronal health, summarize advances in defining the cellular pathological phenotype caused by retromer deficiency or PD-linked retromer variants and discuss the potential clues of how retromer deregulation may contribute to PD pathogenesis.Keywords: autophagy; endosomal trafficking; lysosome; mitochondria; Parkinson's disease (PD); retromer The endosomal network is a highly dynamic and orchestrated system, which serves a vital function in coordinating the communication and exchange of associated proteins and lipids between intracellular membrane-bounded compartments. Once within the network, cargo molecules originating from the plasma membrane and biosynthetic pathways are targeted to a common sorting station, the early endosome, from where cargoes are sorted towards specialized intracellular locations following multiple trafficking routes. They can be either sorted into late endosomes/ lysosomes for degradation or retrieved to the plasma membrane or the trans-Golgi network (TGN). The efficient and accurate delivery of cargo contents within intracellular compartments is critical for the maintenance of intracellular homeostasis, and defects on it are often associated with multiple human diseases. The evolutionary conserved protein complex, termed Abbreviations AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; APEX, ascorbate peroxidase; APP, b-amyloid precursor protein; ATG9A, autophagy-associated protein; Ab, elevated b-amyloid peptide; BAR, Bin-Amphiphysin-Rvs; BDNF, brain-derived neurotrophic factor; CI-M6PR, cation-independent mannose 6-phosphate receptor; CLN5, ceroid lipouscinosis neuronal protein-5; CMA, chaperon-mediated autophagy; Crb, crumb; DA, dopaminergic; DMTI-II, divalent metal transporter II; DRD1, dopamine receptor D1; Drp1, dynamin-related protein 1; EHD1, Eps15 homology domain-containing protein-1; FERM, 4.1/ezrin/radixin/moesin; GLUT1, glucose transporter 1; Kir3, G protein-gated inward rectifying potassium channels; Lamp2a, lysosome-associated membrane glycoprotein 2a; LBs, Lewy bodies; MAPL, mitochondria-anchored protein ligase; MDVs, mitochondria-de...

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Section: Impaired Endolysosomal-mediated Protein Degradationsupporting

confidence: 67%

The functional roles of retromer in Parkinson's disease

2017

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“…29 A rare missense mutation of VPS35, p.Asp620Asn (D620N), has been found to cause Parkinson disease and results in impaired association of the retromer cargo-selective subcomplex with the WASH complex. 30,31 The L625P mutation is located in the VPS35 C-terminal domain involved in VPS29 binding, similar to the D620N missense mutation. When HeLa cells were transiently transfected with a GFP-tagged VPS35 L625P mutant, the mutation reduced the amount of VPS29 that co-immunoprecipitates with the tagged VPS35 (Figure 2), although the effect was not as pronounced as that of the H675R mutation, a mutation initially characterized in Saccharomyces Cerevisiae that totally abolishes the binding to VPS29.…”

Section: Resultsmentioning

confidence: 98%

De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease

et al. 2015

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We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.

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“…In these cases, depletion of retromer contributes to neurodegeneration through impaired endolysosomal trafficking of certain enzymes responsible for the generation or clearance of aggregation-prone proteins; BACE1, a protease responsible for β-amyloid production in Alzheimer's disease and cathepsin D, the main lysosomal enzyme for α-synuclein degradation in Parkinson's disease, respectively (62,63). Additionally, the D620 mutant, Parkinson's disease-linked form of Vps35 is the subject of intensive research, however data from various groups are contradictory regarding the loss-or gain-of-function nature of this allele and its exact effects on intracellular trafficking (64,65). It is evident though that this mutant allele does not represent a null mutation, but it has serious effects on neurotransmitter receptor trafficking in vitro and causes neurodegeneration and loss of locomotor activity in vivo (66)(67)(68).…”

Section: Figure 8: Function Of Retromer In Normal Cells (A) and The Ementioning

confidence: 99%

Retromer Ensures the Degradation of Autophagic Cargo by Maintaining Lysosome Function in Drosophila

Maruzs

Lőrincz

Szatmári

et al. 2015

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The retromer is an evolutionarily conserved coat complex that consists of Vps26, Vps29, Vps35 and a heterodimer of sorting nexin (Snx) proteins in yeast. Retromer mediates the recycling of transmembrane proteins from endosomes to the trans-Golgi network, including receptors that are essential for the delivery of hydrolytic enzymes to lysosomes.Besides its function in lysosomal enzyme receptor recycling, involvement of retromer has also been proposed in a variety of vesicular trafficking events, including early steps of autophagy and endocytosis. Here we show that the late stages of autophagy and endocytosis are impaired in Vps26 and Vps35 deficient Drosophila larval fat body cells, but formation of autophagosomes and endosomes is not compromised. Accumulation of aberrant autolysosomes and amphisomes in the absence of retromer function appears to be the consequence of decreased degradative capacity, as they contain undigested cytoplasmic material.Accordingly, we show that retromer is required for proper cathepsin L trafficking mainly independent of LERP, the Drosophila homolog of the cation-independent mannose 6-phosphate receptor. Finally, we find that Snx3 and Snx6 are also required for proper autolysosomal degradation in Drosophila larval fat body cells.

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Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation

Cited by 43 publications

References 0 publications

The functional roles of retromer in Parkinson's disease

The functional roles of retromer in Parkinson's disease

De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease

Retromer Ensures the Degradation of Autophagic Cargo by Maintaining Lysosome Function in Drosophila

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