LE GUEN, Yann; LUO, Guo; AMBATI, Aditya; DAMOTTE, Vincent; JANSEN, Iris; YU, Eric; NICOLAS, Aude; DE ROJAS, Itziar; PEIXOTO LEAL, Thiago; MIYASHITA, Akinori; BELLENGUEZ, Celine; LIAN, Michelle Mulan; PARVEEN, Kayenat; MORIZONO, Takashi; PARK, Hyeonseul; GRENIER-BOLEY, Benjamin; NAITO, Tatsuhiko; KUCUKALI, Fahri; TALYANSKY, Seth D; YOGESHWAR, Selina Maria; SEMPERE, Vicente; SATAKE, Wataru; ALVAREZ, Victoria; AROSIO, Beatrice; BELLOY, Michael E; BENUSSI, Luisa; BOLAND, Anne; BORRONI, Barbara; BULLIDO, Maria J; CAFFARRA, Paolo; CLARIMON, Jordi; DANIELE, Antonio; DARLING, Daniel; DEBETTE, Stephanie; DELEUZE, Jean-Francois; DICHGANS, Martin; DUFOUIL, Carole; DURING, Emmanuel; DUZEL, Emrah; GALIMBERTI, Daniela; GARCIA-RIBAS, Guillermo; GARCIA-ALBERCA, Jose Maria; GARCIA-GONZALEZ, Pablo; GIEDRAITIS, Vilmantas; GOLDHARDT, Oliver; GRAFF, Caroline; GRUNBLATT, Edna; HANON, Olivier; HAUSNER, Lucrezia; HEILMANN-HEIMBACH, Stefanie; HOLSTEGE, Henne; HORT, Jakub; JUNG, Yoo Jin; JURGEN, Deckert; KERN, Silke; KUULASMAA, Teemu; LEE, Kun Ho; LIN, Ling; MASULLO, Carlo; MECOCCI, Patrizia; MEHRABIAN, Shima; DE MENDONCA, Alexandre; BOADA, Merce; MIR, Pablo; MOEBUS, Susanne; MORENO, Fermin; NACMIAS, Benedetta; NICOLAS, Gael; NIIDA, Shumpei; NORDESTGAARD, Borge G; PAPENBERG, Goran; PAPMA, Janne; PARNETTI, Lucilla; PASQUIER, Florence; PASTOR, Pau; PETERS, Oliver; PIJNENBURG, Yolande A L; PINOL-RIPOLL, Gerard; POPP, Julius; PORCEL, Laura Molina; PUERTA, Raquel; PEREZ-TUR, Jordi; RAINERO, Innocenzo; RAMAKERS, Inez; REAL, Luis M; RIEDEL-HELLER, Steffi; RODRIGUEZ-RODRIGUEZ, Eloy; ROSS, Owen A; ROYO, Luis Jose; RUJESCU, Dan; SCARMEAS, Nikolaos; SCHELTENS, Philip; SCHERBAUM, Norbert; SCHNEIDER, Anja; SERIPA, Davide; SKOOG, Ingmar; SOLFRIZZI, Vincenzo; SPALLETTA, Gianfranco; SQUASSINA, Alessio; VAN SWIETEN, John; SANCHEZ-VALLE, Raquel; TAN, Eng-King; TEGOS, Thomas; TEUNISSEN, Charlotte; THOMASSEN, Jesper Qvist; TREMOLIZZO, Lucio; VYHNALEK, Martin; VERHEY, Frans; WAERN, Margda; WILTFANG, Jens; ZHANG, Jing; ZETTERBERG, Henrik; BLENNOW, Kaj; HE, Zihuai; WILLIAMS, Julie; AMOUYEL, Philippe; JESSEN, Frank; KEHOE, Patrick G; ANDREASSEN, Ole A; VAN DUIN, Cornelia; TSOLAKI, Magda; SANCHEZ-JUAN, Pascual; FRIKKE-SCHMIDT, Ruth; SLEEGERS, Kristel; TODA, Tatsushi; ZETTERGREN, Anna; INGELSSON, Martin; OKADA, Yukinori; ROSSI, Giacomina; HILTUNEN, Mikko; GIM, Jungsoo; OZAKI, Kouichi; SIMS, Rebecca; FOO, Jia Nee; VAN DER FLIER, Wiesje; IKEUCHI, Takeshi; RAMIREZ, Alfredo; MATA, Ignacio; RUIZ, Agustin; GAN-OR, Ziv; LAMBERT, Jean-Charles; GREICIUS, Michael D; MIGNOT, Emmanuel

doi:10.1073/pnas.2302720120

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Proceedings of the National Academy of Sciences of the United States of America. 2023-09-05, vol. 120, n° 36, p. e2302720120

Resumen en inglés

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.< Leer menos

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Alzheimer’s Dementia

HLA

Parkinson’s Disease

Autoimmunity

Neurodegeneration

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https://oskar-bordeaux.fr/handle/20.500.12278/199971

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http://dx.doi.org/10.1073/pnas.2302720120

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Bordeaux Population Health Research Center (BPH) - UMR 1219

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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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Palabras clave en inglés

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