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https://www.readbyqxmd.com/read/29777037/inhibition-of-tbc1d5-activates-rab7a-and-can-enhance-the-function-of-the-retromer-cargo-selective-complex
#1
Matthew N J Seaman, Aamir S Mukadam, Sophia Y Breusegem
The retromer complex is a vital component of the endosomal protein sorting machinery being necessary for sorting into both the endosome-to-Golgi retrieval pathway and also the endosome-to-cell-surface recycling pathway. Retromer mediates cargo selection through a trimeric complex comprising VPS35, VPS29 and VPS26 which is recruited to endosomes by binding to Rab7a and Snx3. Retromer function is linked to two distinct neurodegenerative diseases, Parkinson's disease and Alzheimer's disease and modulating retromer function has been proposed as an avenue to explore for a putative therapy in these conditions...
May 18, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29755290/retromer-dysfunction-and-neurodegenerative-disease
#2
REVIEW
Christiane Reitz
In recent years, genomic, animal and cell biology studies have implicated deficiencies in retromer-mediated trafficking of proteins in an increasing number of neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Frontotemporal Lobar Degener-ation (FTLD). The retromer complex, which is highly conserved across all eukaryotes, regulates the sorting of transmembrane proteins out of endo-somes to the cell surface or to the trans-Golgi network. Within retromer, cargo selection and binding are performed by a trimer of the Vps26, Vps29 and Vps35 proteins, named the "Cargo-Selective Complex (CSC)"...
May 2018: Current Genomics
https://www.readbyqxmd.com/read/29743203/the-parkinson-s-disease-vps35-d620n-mutation-enhances-lrrk2-mediated-rab-protein-phosphorylation-in-mouse-and-human
#3
Rafeeq Mir, Francesca Tonelli, Pawel Lis, Thomas Macartney, Nicole K Polinski, Terina N Martinez, Meng-Yun Chou, Andrew J M Howden, Theresa König, Christoph Hotzy, Ivan Milenkovic, Thomas Brücke, Alexander Zimprich, Esther Sammler, Dario R Alessi
Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson's disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts...
May 9, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29719505/cellular-and-molecular-basis-of-neurodegeneration-in-parkinson-disease
#4
REVIEW
Xian-Si Zeng, Wen-Shuo Geng, Jin-Jing Jia, Lei Chen, Peng-Peng Zhang
It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the pathogenesis of PD is still unknown, the research findings from scientists are conducive to understand the pathological mechanisms. It is well accepted that both genetic and environmental factors contribute to the onset of PD. In this review, we summarize the mutations of main seven genes (α-synuclein, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1) linked to PD, discuss the potential mechanisms for the loss of dopaminergic neurons (dopamine metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, and deregulation of immunity) in PD, and expect the development direction for treatment of PD...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29668757/actin-polymerization-in-the-endosomal-pathway-but-not-on-the-coxiella-containing-vacuole-is-essential-for-pathogen-growth
#5
Heather E Miller, Charles L Larson, Robert A Heinzen
Coxiella burnetii is an intracellular bacterium that replicates within an expansive phagolysosome-like vacuole. Fusion between the Coxiella-containing vacuole (CCV) and late endosomes/multivesicular bodies requires Rab7, the HOPS tethering complex, and SNARE proteins, with actin also speculated to play a role. Here, we investigated the importance of actin in CCV fusion. Filamentous actin patches formed around the CCV membrane that were preferred sites of vesicular fusion. Accordingly, the mediators of endolysosomal fusion Rab7, VAMP7, and syntaxin 8 were concentrated in CCV actin patches...
April 18, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29663589/tying-trafficking-to-fusion-and-fission-at-the-mighty-mitochondria
#6
REVIEW
Trey Farmer, Naava Naslavsky, Steve Caplan
The mitochondrion is a unique organelle that serves as the main site of adenosine triphosphate (ATP) generation needed for energy in the cell. However, mitochondria also play essential roles in cell death through apoptosis and necrosis, as well as a variety of crucial functions related to stress regulation, autophagy, lipid synthesis, and calcium storage. There is a growing appreciation that mitochondrial function is regulated by the dynamics of its membrane fusion and fission; longer, fused mitochondria are optimal for ATP generation, whereas fission of mitochondria facilitates mitophagy and cell division...
April 16, 2018: Traffic
https://www.readbyqxmd.com/read/29602783/quantitative-imaging-flow-cytometry-of-legionella-infected-dictyostelium-reveals-the-impact-of-retrograde-trafficking-on-pathogen-vacuole-composition
#7
Amanda Welin, Stephen Weber, Hubert Hilbi
The ubiquitous environmental bacterium Legionella pneumophila survives and replicates within amoebae and human macrophages by forming a Legionella -containing vacuole (LCV). In an intricate process governed by the bacterial Icm/Dot type IV secretion system and a plethora of "effector proteins" the nascent LCV interferes with a number of intracellular trafficking pathways, including retrograde transport from endosomes to the Golgi apparatus. Conserved retrograde trafficking components such as the retromer coat complex or the phosphoinositide (PI) 5-phosphatase Dd5P4/OCRL restrict intracellular replication of L...
March 30, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29445238/vps35-depletion-does-not-impair-presynaptic-structure-and-function
#8
Sonia Vazquez-Sanchez, Sander Bobeldijk, Marien P Dekker, Linda van Keimpema, Jan R T van Weering
The endosomal system is proposed as a mediator of synaptic vesicle recycling, but the molecular recycling mechanism remains largely unknown. Retromer is a key protein complex which mediates endosomal recycling in eukaryotic cells, including neurons. Retromer is important for brain function and mutations in retromer genes are linked to neurodegenerative diseases. In this study, we aimed to determine the role of retromer in presynaptic structure and function. We assessed the role of retromer by knocking down VPS35, the core subunit of retromer, in primary hippocampal mouse neurons...
February 14, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29329938/pipeline-to-gene-discovery-analysing-familial-parkinsonism-in-the-queensland-parkinson-s-project
#9
Steven R Bentley, Stephanie Bortnick, Ilaria Guella, Javed Y Fowdar, Peter A Silburn, Stephen A Wood, Matthew J Farrer, George D Mellick
INTRODUCTION: Family based study designs provide an informative resource to identify disease-causing mutations. The Queensland Parkinson's Project (QPP) has been involved in numerous genetic screening studies; however, details of the families enrolled into the register have not been comprehensively reported. This article characterises the families enrolled in the QPP and summarises monogenic forms of hereditary Parkinsonism found in the register. METHOD: The presence of pathogenic point mutations and copy number variations (CNVs) were, generally, screened in a sample of over 1000 PD patients from the total of 1725...
April 2018: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29325612/genetics-of-parkinson-disease
#10
Aloysius Domingo, Christine Klein
An understanding of the genetic etiology of Parkinson disease (PD) has become imperative for the modern-day neurologist. Although genetic forms cause only a minority of PD, the disease mechanisms they elucidate advance the understanding of idiopathic cases. Moreover, recently identified susceptibility variants contribute to complex-etiology PD and broaden the contribution of genetics beyond familial and early-onset cases. Dominantly inherited monogenic forms mimic idiopathic PD and are caused by mutations or copy number variations of SNCA, LRRK2, and VPS35...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29229824/molecular-mechanism-for-the-subversion-of-the-retromer-coat-by-the-legionella-effector-ridl
#11
Miguel Romano-Moreno, Adriana L Rojas, Chad D Williamson, David C Gershlick, María Lucas, Michail N Isupov, Juan S Bonifacino, Matthias P Machner, Aitor Hierro
Microbial pathogens employ sophisticated virulence strategies to cause infections in humans. The intracellular pathogen Legionella pneumophila encodes RidL to hijack the host scaffold protein VPS29, a component of retromer and retriever complexes critical for endosomal cargo recycling. Here, we determined the crystal structure of L. pneumophila RidL in complex with the human VPS29-VPS35 retromer subcomplex. A hairpin loop protruding from RidL inserts into a conserved pocket on VPS29 that is also used by cellular ligands, such as Tre-2/Bub2/Cdc16 domain family member 5 (TBC1D5) and VPS9-ankyrin repeat protein for VPS29 binding...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29210454/the-functional-roles-of-retromer-in-parkinson-s-disease
#12
REVIEW
Yi Cui, Zhe Yang, Rohan D Teasdale
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...
December 6, 2017: FEBS Letters
https://www.readbyqxmd.com/read/29203636/identification-of-potential-pathogenic-genes-associated-with-osteoporosis
#13
B Xia, Y Li, J Zhou, B Tian, L Feng
OBJECTIVES: Osteoporosis is a chronic disease. The aim of this study was to identify key genes in osteoporosis. METHODS: Microarray data sets GSE56815 and GSE56814, comprising 67 osteoporosis blood samples and 62 control blood samples, were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in osteoporosis using Limma package (3.2.1) and Meta-MA packages. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify biological functions...
December 2017: Bone & Joint Research
https://www.readbyqxmd.com/read/29135085/retromer-and-the-cation-independent-mannose-6-phosphate-receptor-time-for-a-trial-separation
#14
Matthew N J Seaman
The retromer cargo-selective complex (CSC) comprising Vps35, Vps29 and Vps26 mediates the endosome-to-Golgi retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR). Or does it? Recently published data have questioned the validity of this long-established theory. Here, the evidence for and against a role for the retromer CSC in CIMPR endosome-to-Golgi retrieval is examined in the light of the new data that the SNX-BAR dimer is actually responsible for CIMPR retrieval.
February 2018: Traffic
https://www.readbyqxmd.com/read/28985717/identification-of-vps35-p-d620n-mutation-related-parkinson-s-disease-in-a-taiwanese-family-with-successful-bilateral-subthalamic-nucleus-deep-brain-stimulation-a-case-report-and-literature-review
#15
Ying-Fa Chen, Yung-Yee Chang, Min-Yu Lan, Pei-Lung Chen, Chin-Hsien Lin
BACKGROUND: Vacuolar protein sorting 35 (VPS35) was recently reported to be a genetic cause for late-onset autosomal dominant Parkinson's disease (PD). However, VPS35 mutations are rarely reported in Asian populations. Herein, we report the first Taiwanese family with the pathogenic VPS35 p.D620N mutation, including one patient treated successfully with subthalamic nucleus deep brain stimulation (STN-DBS). CASE PRESENTATION: A 61-year-old woman presented with progressive left hand resting tremor at the age of 42...
October 6, 2017: BMC Neurology
https://www.readbyqxmd.com/read/28935632/cargo-selective-snx-bar-proteins-mediate-retromer-trimer-independent-retrograde-transport
#16
Arunas Kvainickas, Ana Jimenez-Orgaz, Heike Nägele, Zehan Hu, Jörn Dengjel, Florian Steinberg
The retromer complex, which recycles the cation-independent mannose 6-phosphate receptor (CI-MPR) from endosomes to the trans-Golgi network (TGN), is thought to consist of a cargo-selective VPS26-VPS29-VPS35 trimer and a membrane-deforming subunit of sorting nexin (SNX)-Bin, Amphyphysin, and Rvs (BAR; SNX-BAR) proteins. In this study, we demonstrate that heterodimers of the SNX-BAR proteins, SNX1, SNX2, SNX5, and SNX6, are the cargo-selective elements that mediate the retrograde transport of CI-MPR from endosomes to the TGN independently of the core retromer trimer...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28934248/vps35-deficiency-impairs-slc4a11-trafficking-and-promotes-corneal-dystrophy
#17
Wei Liu, Fu-Lei Tang, Sen Lin, Kai Zhao, Lin Mei, Jian Ye, Wen-Cheng Xiong
Vps35 (vacuolar protein sorting 35) is a major component of retromer that selectively promotes endosome-to-Golgi retrieval of transmembrane proteins. Dysfunction of retromer is a risk factor for the pathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD). However, Vps35/retromer's function in the eye or the contribution of Vps35-deficiency to eye degenerative disorders remains to be explored. Here we provide evidence for a critical role of Vps35 in mouse corneal dystrophy. Vps35 is expressed in mouse and human cornea...
2017: PloS One
https://www.readbyqxmd.com/read/28802919/nonmotor-signs-in-genetic-forms-of-parkinson-s-disease
#18
Meike Kasten, Connie Marras, Christine Klein
Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, "idiopathic" PD (iPD) can be garnered from monogenic model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28765075/parkinson-s-disease-associated-pathogenic-vps35-mutation-causes-complex-i-deficits
#19
Leping Zhou, Wenzhang Wang, Charles Hoppel, Jun Liu, Xiongwei Zhu
Defect in the complex I of the mitochondrial electron-transport chain is a characteristic of Parkinson's disease (PD) which is thought to play a critical role in the disease pathogenesis. Mutations in vacuolar protein sorting 35 (VPS35) cause autosomal dominant PD and we recently demonstrated that pathogenic VPS35 mutations cause mitochondrial damage through enhanced mitochondrial fragmentation. In this study, we aimed to determine whether pathogenic VPS35 mutation impacts the activity of complex I and its underlying mechanism...
November 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28757549/updated-insight-into-the-physiological-and-pathological-roles-of-the-retromer-complex
#20
REVIEW
Yakubu Saddeeq Abubakar, Wenhui Zheng, Stefan Olsson, Jie Zhou
Retromer complexes mediate protein trafficking from the endosomes to the trans-Golgi network (TGN) or through direct recycling to the plasma membrane. In yeast, they consist of a conserved trimer of the cargo selective complex (CSC), Vps26-Vps35-Vps29 and a dimer of sorting nexins (SNXs), Vps5-Vps17. In mammals, the CSC interacts with different kinds of SNX proteins in addition to the mammalian homologues of Vps5 and Vps17, which further diversifies retromer functions. The retromer complex plays important roles in many cellular processes including restriction of invading pathogens...
July 25, 2017: International Journal of Molecular Sciences
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