DOCSLIB.ORG

Association of Distinct Variants in SORL1 with Cerebrovascular and Neurodegenerative Changes Related to Alzheimer Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Association of Distinct Variants in SORL1 with Cerebrovascular and Neurodegenerative Changes Related to Alzheimer Disease ORIGINAL CONTRIBUTION Association of Distinct Variants in SORL1 With Cerebrovascular and Neurodegenerative Changes Related to Alzheimer Disease Karen T. Cuenco, PhD; Kathryn L. Lunetta, PhD; Clinton T. Baldwin, PhD; Ann C. McKee, MD; Jianping Guo, MS; L. Adrienne Cupples, PhD; Robert C. Green, MD, MPH; Peter H. St. George-Hyslop, MD; Helena Chui, MD; Charles DeCarli, MD; Lindsay A. Farrer, PhD; for the MIRAGE Study Group Background: Single-nucleotide polymorphisms (SNPs) Results: In white patients, white matter hyperintensities in 2 distinct regions of the gene for the sortilin-related were associated with multiple markers in the region en- receptor (SORL1) (bounded by consecutively num- compassing SNPs 6 to 10, whereas cerebral and hippocam- bered SNPs 8-10 and 22-25) were shown to be associ- pal atrophy were associated with markers from the region ated with Alzheimer disease (AD) in multiple ethnically including SNPs 21 to 26. Examination of specific 3-SNP diverse samples. haplotypes from these 2 regions in the autopsy-confirmed cases of AD revealed association of white matter disease with Objective: To test the hypothesis that SORL1 is asso- SNPs 8 to 10 and association of hippocampal atrophy with ciated with brain magnetic resonance imaging (MRI) mea- SNPs 22 to 26. The haplotype CGC at SNPs 8 to 10 was surements of atrophy and/or vascular disease. associated with fewer white matter changes in the clinical (PϽ.001) and autopsy (P=.02) samples. Design, Setting, and Patients: We evaluated the Conclusions: Variants of SORL1 previously associated association of 30 SNPs spanning SORL1 with MRI mea- with AD are also associated with MRI and neuropatho- sures of general cerebral atrophy, hippocampal atro- logical measures of neurodegenerative and cerebrovas- phy, white matter hyperintensities, and overall cerebro- cular disease. These findings not only support the hy- vascular disease in 44 African American and 182 white pothesis that multiple areas in SORL1 are of functional sibships from the MIRAGE Study. We performed single- importance but also raise the possibility that multiple and 3-SNP haplotype association analyses using family- SORL1 variants influence amyloid precursor protein or based tests. Haplotypes found to be significantly associ- endothelial lipoprotein processing or both in different re- ated with at least 1 MRI trait were tested for association gions of the brain. with 6 pathological traits in a separate sample of 69 white patients with autopsy-confirmed AD. Arch Neurol. 2008;65(12):1640-1648 ONVERGING LINES OF EVI- or pathological criteria for AD, whereas the dence have implicated 1 evidence of the association was equivocal in member of the vacuolar another study.11 proteinsorting10family— One hypothesis for the role of SORL1 thesortilin-relatedreceptor, in the pathogenesis of AD is that SORL1 low-densityC lipoprotein receptor class A modulates subcellular trafficking of the repeat-containingprotein(SORL1)(GenBank amyloid precursor protein (APP). Re- 6653)—inthepathogenesisofAlzheimerdis- duced expression of SORL1 may lead to ease (AD).1-3 Pathological studies4,5 have routing of APP into compartments where documented reduced SORL1 expression in it is cleaved by the presenilin 1 complex to the brains of some patients with AD. Asso- generate the amyloid ␤ peptide.3 The role Author Affiliations are listed at ciation between the risk of AD and multiple of SORL1 in APP processing is strongly sup- the end of this article. SORL1 single-nucleotide polymorphisms ported by the fact that SORL1 interacts with Group Information: Members (SNPs) has been demonstrated in several endogenous APP holoproteins3,12 but does of the Multi-Institutional 3,6-10 Research in Alzheimer’s Genetic studies that included populations of di- not bind to APP C-terminal fragments or 3 Epidemiology (MIRAGE) Study verse ethnic background, used various study to other type I membrane proteins. The Group are listed at the end of designs (ie, clinic case-control, family-based, SORL1 protein also belongs to a superfam- this article. or population-based), and relied on clinical ily of low-density lipoprotein receptors (REPRINTED) ARCH NEUROL / VOL 65 (NO. 12), DEC 2008 WWW.ARCHNEUROL.COM 1640 Downloaded from www.archneurol.com at Boston University, on December 8, 2008 ©2008 American Medical Association. All rights reserved. (SorLA/LR11) that bind apolipoprotein E (APOE) and are implicated in cholesterol metabolism13 and atherogen- SORL1 protein TM 14 esis. Human macrophages exposed to SORL1 have el- Epidermal Internal VPS10 B repeats A repeats Fn-III evated lipid levels, and mice genetically deficient for SORL1 growth factor control Vacuolar protein LDLR-like domain show signs of thickening arteries and macrophage infil- sorting domain tration relative to SORL1 knockout controls. These ob- servations suggest a role for SORL1 in the development of atherosclerosis14 and raise the intriguing possibility that, APP processing (Golgi) Cholesterol metabolism (APOE and LRP1) like APOE and other cholesterol metabolism genes (eg, paraoxonase15), SORL1 may also increase dementia risk through effects on cerebrovascular abnormalities. In- Alzheimer Cerebrovascular deed, cerebrovascular disease increases the odds of de- disease disease mentia16 and potentially interacts with AD pathologic mechanisms to alter memory.17 Neurodegenerative and Figure. Inferred biochemical basis for the role of the sortilin-related receptor cerebrovascular processes can be linked to the known pro- SORL1 in Alzheimer disease and cerebrovascular disease. The SORL1 tein structure of SORL1 (Figure). protein contains several functional domains. The N-terminus region of the The possibility of multiple mechanisms of action as- protein contains the vacuolar protein sorting 10 (VPS10) domain, which may be the region of the gene directly involved in amyloid precursor protein sociated with distinct SORL1 polymorphisms is sup- (APP) processing, although the APP binding domain is not yet known. ported by previous association studies. The SNPs asso- SORL1 also contains a low-density lipoprotein receptor (LDLR)–like domain ciated with AD are located in 2 regions in SORL1 separated that is important in cholesterol metabolism. APOE indicates apolipoprotein E; by a mean (SD) of 100 (15) kilobases that contain areas Fn-III, fibronectin type III region; LRP1, low-density lipoprotein–related protein 1; and TM, transmembrane region. of tight linkage disequilibrium in white and African Ameri- can subjects.3,18 Associations with SNPs in the region near the 5Ј end have been reported in white European sub- tus of individuals identified as nondemented was confirmed by a score of 86 or higher on the modified Telephone Interview jects, Hispanic subjects from the Dominican Republic, of Cognitive Status.21 Age at onset of AD was defined as the age and Israeli-Arab subjects,3,6 whereas SNPs in the region Ј at which the earliest symptoms were reported by proxy. Only closer to the 3 end show association in African Ameri- subjects who self-reported their ethnicity as white of Euro- can, Han Chinese, and some white European and His- pean descent or African American and gave written informed panic subjects.3,6,8,10 Furthermore, associations with a spe- consent are included in this study. Study protocols were ap- cific 3-SNP haplotype in each of these locations have been proved by institutional review boards at each recruitment site. replicated in multiple data sets representing several eth- Families with at least 1 affected and 1 unaffected sibling with nic groups.3,6 These results suggest the existence of AD clinical, MRI, and genotype data available for analysis were in- predisposing variants in different functional domains of cluded in this study. An independent sample of 69 patients with SORL1 and thus raise the possibility for variable effects autopsy-confirmed AD (mean [SD] age at death, 75.0 [7.5] years) was identified through the Alzheimer Disease Center of Bos- of intragenic polymorphisms on the biochemical prop- ton University and was obtained from the Edith Norse Rogers erties of SORL1, on its cell-type–specific patterns of ex- Veterans Affairs Medical Center, Bedford, Massachusetts. This pression, or on both. group is a subsample of patients included in a previous neu- To further elucidate how SORL1 gene variants influ- ropathological study of AD22 with complete neuropathologi- ence processes leading to AD, we evaluated the associa- cal data and DNA specimens available for analysis. tion of SORL1 SNPs with brain magnetic resonance imaging (MRI) findings in a multiethnic group of fami- MRI TRAITS lies containing at least 1 sibpair discordant for AD. In ad- dition, we compared SORL1 haplotypes with analogous In the living subjects (those with AD and the unaffected sib- measures of severity of AD and vascular abnormalities lings), MRI scans of the brain were obtained with 1.5-T mag- in a separate group of deceased individuals with patho- netic field strength scanners using a standard protocol of 3-di- logically confirmed AD. mensional T1-weighted high-resolution sequence, a double spin- echo sequence, and a fluid-attenuated inversion recovery sequence. Semiquantitative measures of neurodegeneration and METHODS cerebrovascular disease were derived from digitized brain MRIs using methods previously described.23 These measures were de- signed to be simple to use and have been shown to correlate SUBJECT RECRUITMENT AND CLASSIFICATION linearly with image quantification.24 The MRIs were evaluated by a single rater
Load more

Recommended publications
  • 1 Supporting Information for a Microrna Network Regulates
    Supporting Information for A microRNA Network Regulates Expression and Biosynthesis of CFTR and CFTR-ΔF508 Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fishere, Shaf Keshavjeeh, Kim A. Lennoxi, Ashley M. Jacobii, Scott D. Rosei, Mark A. Behlkei, Michael J. Welshb,c,d,g, Yi Xingb,c,f, Paul B. McCray Jr.a,b,c Author Affiliations: Department of Pediatricsa, Interdisciplinary Program in Geneticsb, Departments of Internal Medicinec, Molecular Physiology and Biophysicsd, Anatomy and Cell Biologye, Biomedical Engineeringf, Howard Hughes Medical Instituteg, Carver College of Medicine, University of Iowa, Iowa City, IA-52242 Division of Thoracic Surgeryh, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada-M5G 2C4 Integrated DNA Technologiesi, Coralville, IA-52241 To whom correspondence should be addressed: Email: [email protected] (M.J.W.); yi- [email protected] (Y.X.); Email: [email protected] (P.B.M.) This PDF file includes: Materials and Methods References Fig. S1. miR-138 regulates SIN3A in a dose-dependent and site-specific manner. Fig. S2. miR-138 regulates endogenous SIN3A protein expression. Fig. S3. miR-138 regulates endogenous CFTR protein expression in Calu-3 cells. Fig. S4. miR-138 regulates endogenous CFTR protein expression in primary human airway epithelia. Fig. S5. miR-138 regulates CFTR expression in HeLa cells. Fig. S6. miR-138 regulates CFTR expression in HEK293T cells. Fig. S7. HeLa cells exhibit CFTR channel activity. Fig. S8. miR-138 improves CFTR processing. Fig. S9. miR-138 improves CFTR-ΔF508 processing. Fig. S10. SIN3A inhibition yields partial rescue of Cl- transport in CF epithelia.
    [Show full text]
  • Independent and Epistatic Effects of Variants in VPS10-D Receptors on Alzheimer Disease Risk and Processing of the Amyloid Precursor Protein (APP)
    Citation: Transl Psychiatry (2013) 3, e256; doi:10.1038/tp.2013.13 & 2013 Macmillan Publishers Limited All rights reserved 2158-3188/13 www.nature.com/tp Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP) C Reitz1,2,3, G Tosto2, B Vardarajan4, E Rogaeva5, M Ghani5, RS Rogers2, C Conrad2, JL Haines6, MA Pericak-Vance7, MD Fallin8, T Foroud9, LA Farrer4,10,11,12,13,14, GD Schellenberg15, PS George-Hyslop5,16,17, R Mayeux1,2,3,18,19,20 and the Alzheimer’s Disease Genetics Consortium (ADGC) Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain- containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer’s disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n ¼ 11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on c-secretase processing of APP.
    [Show full text]
  • Sorcs2-Mediated NR2A Trafficking Regulates Motor Deficits in Huntington’S Disease
    SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease Qian Ma, … , Lino Tessarollo, Barbara L. Hempstead JCI Insight. 2017;2(9):e88995. https://doi.org/10.1172/jci.insight.88995. Research Article Neuroscience Motor dysfunction is a prominent and disabling feature of Huntington’s disease (HD), but the molecular mechanisms that dictate its onset and progression are unknown. The N-methyl-D-aspartate receptor 2A (NR2A) subunit regulates motor skill development and synaptic plasticity in medium spiny neurons (MSNs) of the striatum, cells that are most severely impacted by HD. Here, we document reduced NR2A receptor subunits on the dendritic membranes and at the synapses of MSNs in zQ175 mice that model HD. We identify that SorCS2, a vacuolar protein sorting 10 protein–domain (VPS10P- domain) receptor, interacts with VPS35, a core component of retromer, thereby regulating surface trafficking of NR2A in MSNs. In the zQ175 striatum, SorCS2 is markedly decreased in an age- and allele-dependent manner. Notably, SorCS2 selectively interacts with mutant huntingtin (mtHTT), but not WT huntingtin (wtHTT), and is mislocalized to perinuclear clusters in striatal neurons of human HD patients and zQ175 mice. Genetic deficiency of SorCS2 accelerates the onset and exacerbates the motor coordination deficit of zQ175 mice. Together, our results identify SorCS2 as an interacting protein of mtHTT and demonstrate that impaired SorCS2-mediated NR2A subunit trafficking to dendritic surface of MSNs is, to our knowledge, a novel mechanism contributing to motor coordination deficits of HD. Find the latest version: https://jci.me/88995/pdf RESEARCH ARTICLE SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease Qian Ma,1 Jianmin Yang,2,3 Teresa A.
    [Show full text]
  • Analysis of the Subcellular Localization of Proteins Implicated in Alzheimer's
    Submitted for partial fulfilment of Doctor of Philosophy (PhD) ANALYSIS OF THE SUBCELLULAR LOCALIZATION OF PROTEINS IMPLICATED IN ALZHEIMER’S DISEASE Anne Hwee Ling Lim Supervised by Assoc Prof. Michael Lardelli and Dr. Joan Kelly Department of Genetics and Evolution School of Biological Sciences The University of Adelaide Australia DECLARATION I certify that this work contains no material which has been accepted for the award of any other degree or diploma in my name, in any university or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference has been made in the text. In addition, I certify that no part of this work will, in the future, be used in a submission in my name, for any other degree or diploma in any university or other tertiary institution without the prior approval of the University of Adelaide and where applicable, any partner institution responsible for the joint award of this degree. I give consent to this copy of my thesis when deposited in the University Library, being made available for loan and photocopying, subject to the provisions of the Copyright Act 1968. The author acknowledges that copyright of published works contained within this thesis resides with the copyright holder(s) of those works. I also give permission for the digital version of my thesis to be made available on the web, via the University’s digital research repository, the Library Search and also through web search engines, unless permission has been granted by the University to restrict access for a period of time.
    [Show full text]
  • PSCAN: Spatial Scan Tests Guided by Protein Structures Improve Complex Disease Gene Discovery and Signal Variant Detection
    Tang et al. Genome Biology (2020) 21:217 https://doi.org/10.1186/s13059-020-02121-0 Method Open Access PSCAN: Spatial scan tests guided by protein structures improve complex disease gene discovery and signal variant detection Zheng-Zheng Tang1,2* , Gregory R. Sliwoski3, Guanhua Chen1, Bowen Jin4, William S. Bush4,5, Bingshan Li6* and John A. Capra3,7,8,9* *Correspondence: [email protected]; Abstract [email protected]; Germline disease-causing variants are generally more spatially clustered in protein [email protected] 1Department of Biostatistics and 3-dimensional structures than benign variants. Motivated by this tendency, we develop Medical Informatics, University of a fast and powerful protein-structure-based scan (PSCAN) approach for evaluating Wisconsin-Madison, Madison gene-level associations with complex disease and detecting signal variants. We validate 53715, WI, USA 2Wisconsin Institute for Discovery, PSCAN’s performance on synthetic data and two real data sets for lipid traits and Madison 53715, WI, USA Alzheimer’s disease. Our results demonstrate that PSCAN performs competitively with Full list of author information is available at the end of the article existing gene-level tests while increasing power and identifying more specific signal variant sets. Furthermore, PSCAN enables generation of hypotheses about the molecular basis for the associations in the context of protein structures and functional domains. Keywords: Gene-level association tests, Protein 3D structures, Spatial scan approach, Risk variant detection Background Many whole exome or whole genome sequencing association studies, such as the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program (NHLBI TOPMed) and the National Human Genome Research Institute Genome Sequencing Program (NHGRI GSP), seek to identify genes and variants that influence human com- plex diseases and traits [1–3].
    [Show full text]
  • Network-Based Translation of GWAS Findings to Pathobiology and Drug
    medRxiv preprint doi: https://doi.org/10.1101/2020.01.15.20017160; this version posted January 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease Jiansong Fang1,#, Pengyue Zhang2,#, Quan Wang3,4,#, Yadi Zhou1, Chien-Wei Chiang2, Rui Chen3,4, Bin Zhang1, Bingshan Li3,4, Stephen J. Lewis5, Andrew A. Pieper6, Lang Li2,*, Jeffrey Cummings7,8, Feixiong Cheng1,9,10,* 1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH 43210 3Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37212, USA. 4Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37212, USA. 5Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106, USA 6Harrington Discovery Institute, University Hospital Case Medical Center; Department of Psychiatry, Case Western Reserve University, Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland VAMC, Cleveland, OH 44106, USA 7Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV 89106, USA. 8Department of Brain Health, School of Integrated Health Sciences, University of NOTE:Nevada This preprint Las reports Vegas, new Lasresearch Vegas, that has NV not been89154, certified USA. by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.01.15.20017160; this version posted January 18, 2020.
    [Show full text]
  • View Full Page
    14080 • The Journal of Neuroscience, October 10, 2012 • 32(41):14080–14086 Symposium Vps10 Family Proteins and the Retromer Complex in Aging-Related Neurodegeneration and Diabetes Rachel F. Lane,1 Peter St George-Hyslop,2,3 Barbara L. Hempstead,4 Scott A. Small,5 Stephen M. Strittmatter,6 and Sam Gandy7,8 1Alzheimer’s Drug Discovery Foundation, New York, New York 10019, 2Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 3H2 Canada, 3Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United Kingdom, 4Department of Medicine, Weill Cornell Medical College, New York, New York 10065, 5Department of Neurology and the Taub Institute, Columbia University, School of Physicians and Surgeons, New York, New York 10032, 6Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06536, 7Departments of Neurology and Psychiatry and the Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York New York 10029, and 8James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468 Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer
    [Show full text]
  • Sorcs2 Controls Functional Expression of Amino Acid Transporter EAAT3 to Protect Neurons from Oxidative Stress and Epilepsy-Induced Pathology
    bioRxiv preprint doi: https://doi.org/10.1101/426734; this version posted September 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SorCS2 controls functional expression of amino acid transporter EAAT3 to protect neurons from oxidative stress and epilepsy-induced pathology Anna R. Malik* (1), Kinga Szydlowska (2), Karolina Nizinska (2), Antonino Asaro (1), Erwin A. van Vliet (3, 4), Oliver Popp (1), Gunnar Dittmar (5), Anders Nykjaer (6) Katarzyna Lukasiuk (2), Eleonora Aronica (3, 7), Thomas E. Willnow*,# (1) 1. Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany 2. Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland 3. Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands 4. Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands 5. Department of Oncology, Luxembourg Institute of Health, 1445 Strassen, Luxembourg 6. MIND Center, Danish Research Institute of Translational Neuroscience - DANDRITE, The Danish Research Foundation Center PROMEMO, Departments of Biomedicine, Aarhus University, and Neurosurgery, Aarhus University Hospital, DK-8000C Aarhus Denmark 7. Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW Heemstede, The Netherlands # Lead Contact * Correspondence to: Anna R. Malik Max-Delbrueck-Center for Molecular Medicine Robert-Roessle-Str. 10, D-13125 Berlin, Germany Phone: +49-30-9406-3414 Email: [email protected] Thomas E. Willnow Max-Delbrueck-Center for Molecular Medicine Robert-Roessle-Str. 10, D-13125 Berlin, Germany Phone: +49-30-9406-2569 Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/426734; this version posted September 25, 2018.
    [Show full text]
  • Genome-Wide Association Studies in Alzheimer Disease
    NEUROLOGICAL REVIEW Genome-Wide Association Studies in Alzheimer Disease Stephen C. Waring, DVM, PhD; Roger N. Rosenberg, MD he genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (Ͻ60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (Ն65 years) representing most cases Tof AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to ex- plain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD patho- genesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex dis- eases and represent the next frontier for furthering our understanding of the underlying etiologic, bio- logical, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, al- though early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances.
    [Show full text]
  • And Late-Onset Alzheimer Disease
    SORL1 mutations in early- and late-onset Alzheimer disease Michael L. Cuccaro, ABSTRACT * PhD Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related * Regina M. Carney, MD receptor (SORL1)gene. Yalun Zhang, PhD Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and Christopher Bohm, PhD late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. Brian W. Kunkle, PhD The phenotypic consequences associated with SORL1 mutations were characterized based on Badri N. Vardarajan, PhD clinical reviews of medical records. Functional studies were completed to evaluate b-amyloid Patrice L. Whitehead, BS (Ab) production and amyloid precursor protein (APP) trafficking associated with SORL1 Holly N. Cukier, PhD mutations. Richard Mayeux, MD, SORL1 MSc Results: alterations were present in 2 EOAD families. In one, a SORL1 T588I change Peter St. George-Hyslop, was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, MD an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Margaret A. Pericak- Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M Vance, PhD alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Ab and interfering with APP trafficking. Correspondence to Conclusions: The findings from this study support an important role for SORL1 mutations in AD Dr. Pericak-Vance: [email protected] pathogenesis by way of altering Ab levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation.
    [Show full text]
  • SORL1 Is Genetically Associated with Late-Onset Alzheimer's
    SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians Akinori Miyashita1., Asako Koike2., Gyungah Jun3., Li-San Wang4, Satoshi Takahashi5{, Etsuro Matsubara6, Takeshi Kawarabayashi6, Mikio Shoji6, Naoki Tomita7, Hiroyuki Arai7, Takashi Asada8, Yasuo Harigaya9, Masaki Ikeda10, Masakuni Amari10, Haruo Hanyu11, Susumu Higuchi12, Takeshi Ikeuchi13, Masatoyo Nishizawa13, Masaichi Suga14, Yasuhiro Kawase15, Hiroyasu Akatsu16, Kenji Kosaka16, Takayuki Yamamoto16, Masaki Imagawa17, Tsuyoshi Hamaguchi18, Masahito Yamada18, Takashi Moriaha19, Masatoshi Takeda19, Takeo Takao20, Kenji Nakata21, Yoshikatsu Fujisawa21{, Ken Sasaki21, Ken Watanabe22, Kenji Nakashima23, Katsuya Urakami24, Terumi Ooya25, Mitsuo Takahashi26, Takefumi Yuzuriha27, Kayoko Serikawa28, Seishi Yoshimoto28, Ryuji Nakagawa28, Jong-Won Kim29, Chang-Seok Ki29, Hong-Hee Won29, Duk L. Na30, Sang Won Seo30, Inhee Mook-Jung31, The Alzheimer Disease Genetics Consortium{, Peter St. George-Hyslop32, Richard Mayeux33, Jonathan L. Haines34, Margaret A. Pericak-Vance35, Makiko Yoshida2, Nao Nishida36, Katsushi Tokunaga36, Ken Yamamoto37, Shoji Tsuji38, Ichiro Kanazawa39, Yasuo Ihara40, Gerard D. Schellenberg4, Lindsay A. Farrer3,41"*, Ryozo Kuwano 1" * 1 Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan, 2 Central Research Laboratory, Hitachi Ltd, Tokyo, Japan, 3 Departments of Medicine (Biomedical Genetics), Ophthalmology and Biostatistics, Boston University Schools of Medicine and Public Health,
    [Show full text]
  • Sorting Receptor SORLA – a Trafficking Path to Avoid Alzheimer Disease
    ARTICLE SERIES: Cell Biology and Disease Commentary 2751 Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease Thomas E. Willnow1,* and Olav M. Andersen2,* 1Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany 2The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership, and Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark. *Authors for correspondence ([email protected]; [email protected]) Journal of Cell Science 126, 2751–2760 ß 2013. Published by The Company of Biologists Ltd doi: 10.1242/jcs.125393 Summary Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid b peptides (Ab) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.
    [Show full text]