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UniProt and Alzheimer’s Disease: Linking molecular defects to disease phenotype

Explore the comprehensive protein sequence and functional information related to Alzheimer's Disease, including expert literature curation, protein function, interactions, pathways, and more. Discover the genetic links, disease variants, and the relationship between protein variants and disease phenotype.

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UniProt and Alzheimer’s Disease: Linking molecular defects to disease phenotype

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  1. UniProt and Alzheimer’s Disease:Linking molecular defects to disease phenotype Yvonne Lussi help@uniprot.org

  2. UniProtKB: Universal Protein Knowledgebasea comprehensive, high-quality and freely accessible resource of protein sequence and functional information • Expert literature curation on: • Detailed information on protein function, interactions, pathways etc. • Sequences, including isoforms, disease variants and PTMs • Stable identifiers (accessions) European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge, UK SIB Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland Protein Information Resource (PIR), Washington DC and Delaware, USA

  3. UniProtKB: Universal Protein Knowledgebasea comprehensive, high-quality and freely accessible resource of protein sequence and functional information NIH National Institute of Aging (NIA) medical initiative: Capture information of proteins of impact for human health and biomedical research • Proteins involved in Alzheimer’s Disease • Disease variants European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge, UK SIB Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland Protein Information Resource (PIR), Washington DC and Delaware, USA

  4. Aim of curation project Aim 1: Provide experimental information for proteins involved in AD through literature curation, including the annotation of variants  Curation of >350 AD-related proteins Aim 2: Support network-based navigation of disease-related protein  5000 binary interactions into IntAct Aim 3: Enable the AD research community to fully explore the richness of UniProt functional annotations for the disease  Workshops  Disease Portal

  5. Alzheimer’s disease • Chronic neurodegenerative disorder characterized by progressive dementia • most common form of dementia in the elderly • Accumulation of amyloid-b plaques and neurofibrillary tangles of phospho-tau protein • Degradation of neurons and neuronal dysfunction • Early-onset AD (< 65): APP, PSEN1, PSEN2 • Late-onset AD (> 65): ApoE and others • genetically heterogeneous disorder • Over 450 proteins may have a genetic link to AD Challenge: establishing the relationship between protein variants and disease phenotype

  6. Identification of curation targets • Proteins known to play a functional role in AD pathways, such as Presenilin-1 and Apo-E • Known drug targets for Alzheimer’s (e.g. by querying ChEMBL using relevant Disease Ontology • Proteins that physically interact with those defined in (1) or (2); • Groups of genes showing strong genetic evidence for involvement in Alzheimer’s, such as those showing evidence of epistasis, particularly those that overlap with (1), (2), or (3). Domain expert input from the ARUK network (Lovering UCL) and the NIA network (Arighi University of Delaware, USA)

  7. Alzheimer’s Disease: Pathways and Processes Cytoskeleton Neuronal Synapses MAPT/TAU DBN1 PLEC Apoptosis APP PSEN1 PSEN2 Endocytosis Neurofibrillary Tangles CD2AP PICALM SORL1 BIN1 Hyperphosphorylation of Tau Tau p Lipid metabolism APP APP APOE ABCA7 CLU SORL1 DSG2 b- Secretase AICD Inflammatory response g- Secretase Amyloid Plaques Ab Misfolding Aggregation CLU, ABCA7, CD33, CR1, TREM2, EPHA1, MEF2C. MS4A, INPP5D, HLA-DRB5/HLA-DRB1 Ab40/42 Microglia activation Transcription regulation AMPAR NMDAR nAChR mAChR Glucose Transporter ROS Formation Inflammatory Cytokines Lipid peroxidation Apoptosis REST HABP4 RXRA Membrane damage Oxidative stress

  8. Hompage: Search Free text search bar Default search is UniProtKB Diseases access tab

  9. Example: Presenilin-1 Contact us: help@uniprot.org Quick access tabs list entry contents- click to jump to and/or (de)select to toggle content visibility

  10. Example: Presenilin-1

  11. Publications and references Publications referenced throughout entry using their PubMed identifiers List of publications accessed through quick access tab

  12. Publications viewer An expanded publications view incorporating filters and access to mapped publications. Hyperlinks to the article in PubMed and Europe PMC List of entries that also cite article Indicate the information/data obtained from article and included in entry

  13. Example: Presenilin-1

  14. Binary Interactions in IntAct

  15. Pathology & Biotech

  16. Disease-associated variants Variant evidence Variant Position Database cross-references Variant identifier Disease Association NCBI dbSNP Variant specific comments Amino acid change

  17. Presenilin-1: Variant Leu-453

  18. Feature Viewer

  19. Feature Viewer • Functional • consequence • of variant

  20. Feature Viewer Impact of variant on structure

  21. Summary • New insights into the molecular function of proteins associated with Alzheimer’s disease and disease mechanisms • Relation between variants and disease and linking molecular defects to disease • Network of proteins and interactions underlying disease development • Overview for researchers in the field of neurodegeneration, clinicians and biomedical researchers

  22. Disease Portal: Outlook

  23. Accessing UniProt Data • UniProt Releases every 4 weeks and is freely available - http://www.uniprot.org/downloads • Provided in a range of formats - text, XML, XML/RDF, FASTA, GFF, tab-delimited • Web site • Supports simple and complex queries • RESTful API • Documentation and Details at: http://uniprot.org/help/programmatic_access

  24. UniProt funding This work was supported by the National Eye Institute (NEI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and National Institute of Mental Health (NIMH) of the National Institutes of Health under Award Number [U24HG007822] (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health).  Research reported in this publication was supported by the National Human Genome Research Institute (NHGRI) and the National Institute on Aging (NIA) of the National Institutes of Health under Award Number [3U24HG007822-05S1] (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health). National Institutes of Health

  25. UniProt Team PIs: Alex Bateman,Alan Bridge, Cathy Wu Key staff: Cecilia Arighi (Curation), Lionel Breuza (Curation), Elisabeth Coudert (Curation), Hongzhan Huang (Development),Damien Lieberherr (Curation),Michele Magrane (Curation), Maria Martin (Development),Peter McGarvey (Content), Darren Natale (Content),Sandra Orchard (Content),Ivo Pedruzzi (Curation), Sylvain Poux (Curation), Manuela Pruess (Coordination),Shriya Raj (Coordination),Nicole Redaschi (Development) Content / Curation: Lucila Aimo, Ghislaine Argoud-Puy, Andrea Auchincloss, Kristian Axelsen, Emmanuel Boutet,Emily Bowler,Ramona Britto, Hema Bye-A-Jee,Cristina Casals-Casas, Anne Estreicher, Livia Famiglietti, Marc Feuermann,John S. Garavelli,Penelope Garmiri, George Georghiou,Arnaud Gos, Nadine Gruaz,Emma Hatton-Ellis,Ursula Hinz, Chantal Hulo, NevilaHyka-Nouspikel, Florence Jungo, Kati Laiho,Philippe Lemercier, Yvonne Lussi, Alistair MacDougall,Patrick Masson, Anne Morgat, Sandrine Pilbout, Catherine Rivoire,Karen Ross,Christian Sigrist,Elena Speretta,Shyamala Sundaram, Nidhi Tyagi,C. R. Vinayaka,Qinghua Wang,Kate Warner,Lai-Su Yeh,Rossana Zaru Development: Shadab Ahmed, Emanuele Alpi,Leslie Arminski,Parit Bansal, Delphine Baratin, Teresa Batista Neto,JervenBolleman,BorisasBursteinas,Chuming Chen,Yongxing Chen,Beatrice Cuche,Alan Da Silva,Edouard De Castro,Tunca Dogan, Leyla Garcia Castro,Elisabeth Gasteiger, Sebastien Gehant,Leonardo Gonzales,AlexandrIgnatchenko, Giuseppe Insana, Rizwan Ishtiaq, Vishal Joshi, Dushyanth Jyothi,Arnaud Kerhornou, Thierry Lombardot, Jie Luo, Mahdi Mahmoudy,Andrew Nightingale, Joseph Onwubiko,Monica Pozzato,SangyaPundir, Guoying Qi, Daniel Rice, Rabie Saidi, Edward Turner, Preethi Vasudev, Vladimir Volynkin, Yuqi Wang,Xavier Watkins, Hermann Zellner,Jian Zhang SIB Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland Protein Information Resource (PIR), Washington DC and Delaware, USA European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge, UK

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