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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

Abstract: 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 AB42. 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

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Proceedings of the National Academy of Sciences of the United States of America, 2023, 120(36), e2302720120

Editorial: National Academy of Sciences

 Año de publicación: 2023

Nº de páginas: 11

Tipo de publicación: Artículo de Revista

 DOI: 10.1073/pnas.2302720120

ISSN: 0027-8424,1091-6490

Url de la publicación: https://doi.org/10.1073/pnas.2302720120

Autores/as

LE GUEN, YANN

LUO, GUO

AMBATI, ADITYA

DAMOTTE, VINCENT

JANSEN IRIS

YU, ERICK

NICOLAS, AUDE

DE ROJAS, ITZIAR

PEIXOTO LEAL, THIAGO

MIYASHITA, AKINORI

BELLENGUEZ, CÉLINE

MULAN LIAN, MICHELLE

PARVEEN, KAYENAT

MORIZONO, TAKASHI

PARK, HYEONSEUL

GRENIER-BOLEY, BENJAMIN

NAITO, TATSUHIKO

KÜÇÜKALI, FHARI

TALYANSKY, SETH D.