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Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson's disease.

ABSTRACT: We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson's disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson's disease patient-control series for the VPS29 and VPS26A/B genes. We identified only 2 rare nonsynonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson's disease.

SUBMITTER: Shannon B

PROVIDER: S-EPMC4023811 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson's disease.

Shannon Barbara B Soto-Ortolaza Alexandra A Rayaprolu Sruti S Cannon Heather D HD Labbé Catherine C Benitez Bruno A BA Choi Jiyoon J Lynch Timothy T Boczarska-Jedynak Magdalena M Opala Grzegorz G Krygowska-Wajs Anna A Barcikowska Maria M Van Gerpen Jay A JA Uitti Ryan J RJ Springer Wolfdieter W Cruchaga Carlos C Wszolek Zbigniew K ZK Ross Owen A OA

Neurobiology of aging 20140305 8

We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson's disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson's disease patient-control series for the VPS29 and VPS26A/B genes. We identified only 2 rare nonsynonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson's disease. ...[more]

PMID: 24684791

Similar Datasets

Human genetic variation and Parkinson's disease.

Project description:Parkinson's disease (PD) is a chronic neurodegenerative disorder with multifactorial etiology. In the past decade, the genetic causes of monogenic forms of familial PD have been defined. However, the etiology and pathogenesis of the majority of sporadic PD cases that occur in outbred populations have yet to be clarified. The recent development of resources such as the International HapMap Project and technological advances in high-throughput genotyping have provided new basis for genetic association studies of common complex diseases, including PD. A new generation of genome-wide association studies will soon offer a potentially powerful approach for mapping causal genes and will likely change treatment and alter our perception of the genetic determinants of PD. However, the execution and analysis of such studies will require great care.

| S-EPMC4027658 | biostudies-literature

VPS35, the Retromer Complex and Parkinson's Disease.

Project description:Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies. In this review, we focus on the current knowledge surrounding VPS35 and its role in PD. We provide a critical discussion of the emerging data regarding the mechanisms underlying mutant VPS35-mediated neurodegeneration gleaned from genetic cell and animal models and highlight recent advances that may provide insight into the interplay between VPS35 and several other PD-linked gene products (i.e. α-synuclein, LRRK2 and parkin) in PD. Present data support a role for perturbed VPS35 and retromer function in the pathogenesis of PD.

| S-EPMC5438477 | biostudies-literature

Evolutionary variations of VPS29, and their implications for the heteropentameric model of retromer.

Project description:The retromer complex is conserved across all eukaryotic species and functions in physiologically important sorting processes at the endosomal membrane. A key component of retromer is the VPS29 protein that, although structurally similar to phospho-diesterases, has been convincingly shown in the recent study by Swarbrick et al. (PLoS One 6:e20420, 2011) to be a rigid scaffold that interacts with various proteins that function with retromer in endosomal protein sorting. A widely held view, based on initial observations in Saccharomyces cerevisiae, is that retromer functions as a stable heteropentamer. This is, however, contrary to experimental data presented in Swarbrick et al. (and in other studies) that indicate that retromer in higher eukaryotes is a looser association of two subcomplexes that respectively mediate cargo-selection and membrane tubulation. Here we present an analysis of evolutionary variation of the VPS29 protein and discuss why the retromer complex as first characterized in S. cerevisiae is not representative of retromer in other eukaryotic taxa.

| S-EPMC3204146 | biostudies-literature

Genetic variation of Omi/HtrA2 and Parkinson's disease.

Project description:Variants in the Omi/HtrA2 gene have been nominated as a cause of Parkinson's disease. This sequencing study of Omi/HtrA2 in 95 probands with apparent autosomal dominant inheritance of Parkinson's disease did not identify any pathogenic mutations. In addition, there was no association between common variations in the Omi/HtrA2 gene and susceptibility to Parkinson's disease in any of our four patient-control series (n=2373). Taken together our results do not support a role for Omi/HtrA2 variants in the pathogenesis of Parkinson's disease.

| S-EPMC2614082 | biostudies-literature

Structural insights into Legionella RidL-Vps29 retromer subunit interaction reveal displacement of the regulator TBC1D5.

Project description:Legionella pneumophila can cause Legionnaires' disease and replicates intracellularly in a distinct Legionella-containing vacuole (LCV). LCV formation is a complex process that involves a plethora of type IV-secreted effector proteins. The effector RidL binds the Vps29 retromer subunit, blocks retrograde vesicle trafficking, and promotes intracellular bacterial replication. Here, we reveal that the 29-kDa N-terminal domain of RidL (RidL2-281) adopts a "foot-like" fold comprising a protruding β-hairpin at its "heel". The deletion of the β-hairpin, the exchange to Glu of Ile170 in the β-hairpin, or Leu152 in Vps29 abolishes the interaction in eukaryotic cells and in vitro. RidL2-281 or RidL displace the Rab7 GTPase-activating protein (GAP) TBC1D5 from the retromer and LCVs, respectively, and TBC1D5 promotes the intracellular growth of L. pneumophila. Thus, the hydrophobic β-hairpin of RidL is critical for binding of the L. pneumophila effector to the Vps29 retromer subunit and displacement of the regulator TBC1D5.

| S-EPMC5691146 | biostudies-literature

Retromer-mediated recruitment of the WASH complex involves discrete interactions between VPS35, VPS29, and FAM21.

Project description:Endosomal trafficking ensures the proper distribution of lipids and proteins to various cellular compartments, facilitating intracellular communication, nutrient transport, waste disposal, and the maintenance of cell structure. Retromer, a peripheral membrane protein complex, plays an important role in this process by recruiting the associated actin-polymerizing WASH complex to establish distinct sorting domains. The WASH complex is recruited through the interaction of the VPS35 subunit of retromer with the WASH complex subunit FAM21. Here, we report the identification of two separate fragments of FAM21 that interact with VPS35, along with a third fragment that binds to the VPS29 subunit of retromer. The crystal structure of VPS29 bound to a peptide derived from FAM21 shows a distinctive sharp bend that inserts into a conserved hydrophobic pocket with a binding mode similar to that adopted by other VPS29 effectors. Interestingly, despite the network of interactions between FAM21 and retromer occurring near the Parkinson's disease-linked mutation (D620N) in VPS35, this mutation does not significantly impair the direct association with FAM21 in vitro.

| S-EPMC11010949 | biostudies-literature

Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain.

Project description:Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson's and Alzheimer's disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.

| S-EPMC7182434 | biostudies-literature

Genetic variation of CHRNA4 does not modulate attention in Parkinson's disease.

Project description:Parkinson's disease (PD) is a neurodegenerative disorder, characterised by cognitive decline and attentional impairment. Recently, variation in CHRNA4 (rs1044396) has been shown to affect visual and auditory function, affecting speed and attention, in healthy adults. An association between CHRNA4 variation and PD has not been shown. To determine the link between CHRNA4 variation and attentional deficit in PD. A genotype-phenotype correlation between the common CHRNA4:rs1044396 variant and several baseline parameters of attention was carried out in a large cohort of PD cases (n=222) and controls (n=159). We identified significant associations to measures of attention in PD patients compared to controls. However, we found no significant link to CHRNA4:rs1044396 genotypes to baseline attention variables in PD or in controls. We conclude that CHRNA4:rs1044396 genotypes do not significantly influence the attentional deficit found in PD patients. Contrary to previous studies, we also found no significant influence in healthy age-matched controls.

| S-EPMC4038490 | biostudies-literature

The human Vps29 retromer component is a metallo-phosphoesterase for a cation-independent mannose 6-phosphate receptor substrate peptide.

Project description:The retromer complex is involved in the retrograde transport of the CI-M6PR (cation-independent mannose 6-phosphate receptor) from endosomes to the Golgi. It is a hetero-trimeric complex composed of Vps26 (vacuolar sorting protein 26), Vps29 and Vps35 proteins, which are conserved in eukaryote evolution. Recently, elucidation of the crystal structure of Vps29 revealed that Vps29 contains a metallo-phosphoesterase fold [Wang, Guo, Liang, Fan, Zhu, Zang, Zhu, Li, Teng, Niu et al. (2005) J. Biol. Chem. 280, 22962-22967; Collins, Skinner, Watson, Seaman and Owen (2005) Nat. Struct. Mol. Biol. 12, 594-602]. We demonstrate that recombinant hVps29 (human Vps29) displays in vitro phosphatase activity towards a serine-phosphorylated peptide, containing the acidic-cluster dileucine motif of the cytoplasmatic tail of the CI-M6PR. Efficient dephosphorylation required the additional presence of recombinant hVps26 and hVps35 proteins, which interact with hVps29. Phosphatase activity of hVps29 was greatly decreased by alanine substitutions of active-site residues that are predicted to co-ordinate metal ions. Using inductively coupled plasma MS, we demonstrate that recombinant hVps29 binds zinc. Moreover, hVps29-dependent phosphatase activity is greatly reduced by non-specific and zinc-specific metal ion chelators, which can be completely restored by addition of excess ZnCl2. The binuclear Zn2+ centre and phosphate group were modelled into the hVps29 catalytic site and pKa calculations provided further insight into the molecular mechanisms of Vps29 phosphatase activity. We conclude that the retromer complex displays Vps29-dependent in vitro phosphatase activity towards a serinephosphorylated acidic-cluster dileucine motif that is involved in endosomal trafficking of the CI-M6PR. The potential significance of these findings with respect to regulation of transport of cycling trans-Golgi network proteins is discussed.

| S-EPMC1559457 | biostudies-literature

VPS29 is not an active metallo-phosphatase but is a rigid scaffold required for retromer interaction with accessory proteins.

Project description:VPS29 is a key component of the cargo-binding core complex of retromer, a protein assembly with diverse roles in transport of receptors within the endosomal system. VPS29 has a fold related to metal-binding phosphatases and mediates interactions between retromer and other regulatory proteins. In this study we examine the functional interactions of mammalian VPS29, using X-ray crystallography and NMR spectroscopy. We find that although VPS29 can coordinate metal ions Mn(2+) and Zn(2+) in both the putative active site and at other locations, the affinity for metals is low, and lack of activity in phosphatase assays using a putative peptide substrate support the conclusion that VPS29 is not a functional metalloenzyme. There is evidence that structural elements of VPS29 critical for binding the retromer subunit VPS35 may undergo both metal-dependent and independent conformational changes regulating complex formation, however studies using ITC and NMR residual dipolar coupling (RDC) measurements show that this is not the case. Finally, NMR chemical shift mapping indicates that VPS29 is able to associate with SNX1 via a conserved hydrophobic surface, but with a low affinity that suggests additional interactions will be required to stabilise the complex in vivo. Our conclusion is that VPS29 is a metal ion-independent, rigid scaffolding domain, which is essential but not sufficient for incorporation of retromer into functional endosomal transport assemblies.

| S-EPMC3101248 | biostudies-literature

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