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Corinne D Engelman, Burcu F Darst, Murat Bilgel, Eva Vasiljevic, Rebecca L Koscik, Bruno M Jedynak, Sterling C Johnson
Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer's disease (AD), but their effect on cognitive function is unknown. We examined the effect of these variants on cognitive function in 1449 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of initially asymptomatic adults, aged 36-73 years at baseline, enriched for a parental history of AD. A comprehensive cognitive test battery was performed at up to 5 visits. A factor analysis resulted in 6 cognitive factors that were standardized into z scores (∼N [0, 1]); the mean of these z scores was also calculated...
December 29, 2017: Neurobiology of Aging
Adriana Carolina Gonzalez, Michaela Schweizer, Sebastian Jagdmann, Christian Bernreuther, Thomas Reinheckel, Paul Saftig, Markus Damme
Variants in the phospholipase D3 (PLD3) gene have genetically been linked to late-onset Alzheimer's disease. We present a detailed biochemical analysis of PLD3 and reveal its endogenous localization in endosomes and lysosomes. PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells) uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport) machinery. PLD3 is sorted into intraluminal vesicles of multivesicular endosomes, and ESCRT-dependent sorting correlates with ubiquitination...
January 23, 2018: Cell Reports
Aamir S Mukadam, Sophia Y Breusegem, Matthew N J Seaman
The processing of amyloid precursor protein (APP) to the neurotoxic pro-aggregatory Aβ peptide is controlled by the mechanisms that govern the trafficking and localisation of APP. We hypothesised that genes involved in endosomal protein sorting could play an important role in regulating APP processing and, therefore, analysed ~ 40 novel endosome-to-Golgi retrieval genes previously identified in a genome-wide siRNA screen. We report that phospholipase D3 (PLD3), a type II membrane protein, functions in endosomal protein sorting and plays an important role in regulating APP processing...
January 24, 2018: Cellular and Molecular Life Sciences: CMLS
Esther A R Nibbeling, Anna Duarri, Corien C Verschuuren-Bemelmans, Michiel R Fokkens, Juha M Karjalainen, Cleo J L M Smeets, Jelkje J de Boer-Bergsma, Gerben van der Vries, Dennis Dooijes, Giovana B Bampi, Cleo van Diemen, Ewout Brunt, Elly Ippel, Berry Kremer, Monique Vlak, Noam Adir, Cisca Wijmenga, Bart P C van de Warrenburg, Lude Franke, Richard J Sinke, Dineke S Verbeek
The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons...
November 1, 2017: Brain: a Journal of Neurology
Eugene Lin, Shih-Jen Tsai, Po-Hsiu Kuo, Yu-Li Liu, Albert C Yang, Chung-Feng Kao
Genome-wide association studies and meta-analyses implicated that increased risk of developing Alzheimer's diseases (AD) has been associated with the ABCA7, APOE, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB1, HLA-DRB4, INPP5D, MEF2C, MS4A4A, MS4A4E, MS4A6E, NME8, PICALM, PLD3, PTK2B, RIN3, SLC24A4, SORL1, and ZCWPW1 genes. In this study, we assessed whether single nucleotide polymorphisms (SNPs) within these 27 AD-associatedgenes are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population...
April 11, 2017: Oncotarget
Pietro Fazzari, Katrien Horre, Amaia M Arranz, Carlo Sala Frigerio, Takashi Saito, Takaomi C Saido, Bart De Strooper
No abstract text is available yet for this article.
January 25, 2017: Nature
Elisabet Einarsdottir, Lena Hafrén, Eira Leinonen, Mahmood F Bhutta, Erna Kentala, Juha Kere, Petri S Mattila
To identify genetic risk factors of childhood otitis media (OM), a genome-wide association study was performed on Finnish subjects, 829 affected children, and 2118 randomly selected controls. The most significant and validated finding was an association with an 80 kb region on chromosome 19. It includes the variants rs16974263 (P = 1.77 × 10(-7), OR = 1.59), rs268662 (P = 1.564 × 10(-6), OR = 1.54), and rs4150992 (P = 3.37 × 10(-6), OR = 1.52), and harbors the genes PLD3, SERTAD1, SERTAD3, HIPK4, PRX, and BLVRB, all in strong linkage disequilibrium...
2016: Scientific Reports
Mohan Giri, Man Zhang, Yang Lü
Alzheimer's disease (AD) is a progressive, neurodegenerative disease and the most common form of dementia in elderly people. It is an emerging public health problem that poses a huge societal burden. Linkage analysis was the first milestone in unraveling the mutations in APP, PSEN1, and PSEN2 that cause early-onset AD, followed by the discovery of apolipoprotein E-ε4 allele as the only one genetic risk factor for late-onset AD. Genome-wide association studies have revolutionized genetic research and have identified over 20 genetic loci associated with late-onset AD...
2016: Clinical Interventions in Aging
Yu Chen, Miao Duan, Hai-long Zhou, Kai-ning Shi, Zhao-yong Sun, Chun-mei Bai, Ning Jia, Tao Zhang, Xing-ming Chen, Ke Hu, Zhu-hua Zhang, Zheng-yu Jin
OBJECTIVE: To evaluate the feasibility of three-dimensional pseudo-continuous arterial spin label (3D pCASL) non-contrast enhanced perfusion imaging applied to head and neck tumors in high-field MR and detect the effects of different postlabeling delay (PLD) time on image quality and the reliability of repeated measurements of tumor blood flow (BF) in different 3D pCASL groups. METHODS: In this prospective study,all the 25 patients received neck 3D pCASL non-contrast enhanced perfusion examinations in a 3...
October 2015: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
Rita Cacace, Tobi Van den Bossche, Sebastiaan Engelborghs, Nathalie Geerts, Annelies Laureys, Lubina Dillen, Caroline Graff, Håkan Thonberg, Huei-Hsin Chiang, Pau Pastor, Sara Ortega-Cubero, Maria A Pastor, Janine Diehl-Schmid, Panagiotis Alexopoulos, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Benedetta Nacmias, Sandro Sorbi, Raquel Sanchez-Valle, Albert Lladó, Ellen Gelpi, Maria Rosário Almeida, Isabel Santana, Magda Tsolaki, Maria Koutroumani, Jordi Clarimon, Alberto Lleó, Juan Fortea, Alexandre de Mendonça, Madalena Martins, Barbara Borroni, Alessandro Padovani, Radoslav Matej, Zdenek Rohan, Mathieu Vandenbulcke, Rik Vandenberghe, Peter P De Deyn, Patrick Cras, Julie van der Zee, Kristel Sleegers, Christine Van Broeckhoven
Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries...
December 2015: Human Mutation
Chong Wang, Lan Tan, Hui-Fu Wang, Wan-Jiang Yu, Ying Liu, Teng Jiang, Meng-Shan Tan, Xiao-Ke Hao, Dao-Qiang Zhang, Jin-Tai Yu
The phospholipase D3 (PLD3) gene has shown association with Alzheimer's disease (AD). However, the role of PLD3 common variants in amyloid-β (Aβ) pathology remains unclear. We examined the association of thirteen common single nucleotide polymorphisms (SNPs) with cerebrospinal fluid (CSF) Aβ(1- 42) levels and florbetapir retention on florbetapir 18F amyloid positron emission tomography (AV45-PET) in a large population. We found that one SNP (rs11667768) was significantly associated with CSF Aβ(1- 42) levels in the normal cognition group...
2015: Journal of Alzheimer's Disease: JAD
Julia Stahl, Holger Bergmann, Stephan Göttig, Ingo Ebersberger, Beate Averhoff
Acinetobacter baumannii causes a broad range of opportunistic infections in humans. Its success as an emerging pathogen is due to a combination of increasing antibiotic resistance, environmental persistence and adaptation to the human host. To date very little is known about the molecular basis of the latter. Here we demonstrate that A. baumannii can use phosphatidylcholine, an integral part of human cell membranes, as sole carbon and energy source. We report on the identification of three phospholipases belonging to the PLD superfamily...
2015: PloS One
Jorge L Del-Aguila, Daniel C Koboldt, Kathleen Black, Rachel Chasse, Joanne Norton, Richard K Wilson, Carlos Cruchaga
Recent advances in sequencing technology and novel genotyping arrays (focused on low-frequency and coding variants) have made it possible to identify novel coding variants with large effect sizes and also novel genes (TREM2, PLD3, UNC5C, and AKAP9) associated with Alzheimer's disease (AD) risk. The major advantages of these studies over the classic genome-wide association studies (GWAS) include the identification of the functional variant and the gene-driven association. In addition to the large effect size, these studies make it possible to model these variants and genes using cell and animal systems...
August 2015: Current Opinion in Genetics & Development
Lars Bertram
For the first time in the history of human genetics research, it is now both technically feasible and economically affordable to screen individual genomes for novel disease-causing mutations at base-pair resolution using "next-generation sequencing" (NGS). One popular aim in many of today's NGS studies is genome resequencing (in part or whole) to identify DNA variants potentially accounting for the "missing heritability" problem observed in many genetically complex traits. Thus far, only relatively few projects have applied these powerful new technologies to search for novel Alzheimer's disease (AD) related sequence variants...
2016: Methods in Molecular Biology
Chong Wang, Hui-Fu Wang, Meng-Shan Tan, Ying Liu, Teng Jiang, Dao-Qiang Zhang, Lan Tan, Jin-Tai Yu
Rare variants of phospholipase D3 (PLD3) have been identified as Alzheimer's disease (AD) susceptibility loci, whereas little is known about the potential role of common variants in the progression of AD. To examine the impact of genetic variations in PLD3 on neuroimaging phenotypes in a large non-demented population. A total of 261 normal cognition (NC) and 456 mild cognitive impairment (MCI) individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database are included in our analysis. Multiple linear regression models were applied to examine the association between four single-nucleotide polymorphisms (SNPs; rs7249146, rs4490097, rs12151243, and rs10407447) with the florbetapir retention on florbetapir 18F amyloid positron emission tomography (AV45-PET), the cerebral metabolic rate for glucose (CMRgl) on 18F-fluorodeoxyglucose PET (FDG-PET), and regional volume on magnetic resonance imaging (MRI) at baseline and in the cohort study...
September 2016: Molecular Neurobiology
Deng-Feng Zhang, Yu Fan, Dong Wang, Rui Bi, Chen Zhang, Yiru Fang, Yong-Gang Yao
Alzheimer's disease (AD) is the most common form of dementia. Numerous genome-wide association studies (GWASs) have found several AD susceptibility common loci but with limited effect size. Recent next-generation sequencing studies of large AD pedigrees had identified phospholipase D3 (PLD3) p.V232M as the potentially functional rare variant with causal effect. However, four follow-up replication studies (Brief Communications Arising on Nature) questioned that PLD3 V232M might not be so important in AD. In this study, we re-analyzed all public-available genetic (rare and common variants) and expression data of PLD3, and screened coding variants within PLD3 in probands of 18 Han Chinese families with AD, to clarify the exact involvement of PLD3 in AD...
August 2016: Molecular Neurobiology
Venil N Sumantran, Pratik Mishra, N Sudhakar
A new hallmark of cancer involves acquisition of a lipogenic phenotype which promotes tumorigenesis. Little is known about lipid metabolism in melanomas. Therefore, we used BRB (Biometrics Research Branch) class comparison tool with multivariate analysis to identify differentially expressed genes in human cutaneous melanomas, compared with benign nevi and normal skin derived from the microarray dataset (GDS1375). The methods were validated by identifying known melanoma biomarkers (CITED1, FGFR2, PTPRF, LICAM, SPP1 and PHACTR1) in our results...
April 2015: Indian Journal of Biochemistry & Biophysics
Alessandro Valli, Miguel Rodriguez, Loukas Moutsianas, Roman Fischer, Vita Fedele, Hong-Lei Huang, Ruud Van Stiphout, Dylan Jones, Michael Mccarthy, Maria Vinaxia, Kaori Igarashi, Maya Sato, Tomoyoshi Soga, Francesca Buffa, James Mccullagh, Oscar Yanes, Adrian Harris, Benedikt Kessler
The biochemistry of cancer cells diverges significantly from normal cells as a result of a comprehensive reprogramming of metabolic pathways. A major factor influencing cancer metabolism is hypoxia, which is mediated by HIF1α and HIF2α. HIF1α represents one of the principal regulators of metabolism and energetic balance in cancer cells through its regulation of glycolysis, glycogen synthesis, Krebs cycle and the pentose phosphate shunt. However, less is known about the role of HIF1α in modulating lipid metabolism...
February 10, 2015: Oncotarget
Jun-Ichi Satoh, Yoshihiro Kino, Yoji Yamamoto, Natsuki Kawana, Tsuyoshi Ishida, Yuko Saito, Kunimasa Arima
INTRODUCTION: Recently, a whole-exome sequencing (WES) study showed that a rare variant rs145999145 composed of p.Val232Met located in exon 7 of the phospholipase D3 (PLD3) gene confers a doubled risk for late-onset Alzheimer's disease (AD). Knockdown of PLD3 elevates the levels of extracellular amyloid-beta (Aβ), suggesting that PLD3 acts as a negative regulator of Aβ precursor protein (APP) processing. However, the precise cellular location and distribution of PLD3 in AD brains remain largely unknown...
2014: Alzheimer's Research & Therapy
M Althubiti, L Lezina, S Carrera, R Jukes-Jones, S M Giblett, A Antonov, N Barlev, G S Saldanha, C A Pritchard, K Cain, S Macip
Cellular senescence is a terminal differentiation state that has been proposed to have a role in both tumour suppression and ageing. This view is supported by the fact that accumulation of senescent cells can be observed in response to oncogenic stress as well as a result of normal organismal ageing. Thus, identifying senescent cells in in vivo and in vitro has an important diagnostic and therapeutic potential. The molecular pathways involved in triggering and/or maintaining the senescent phenotype are not fully understood...
November 20, 2014: Cell Death & Disease
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