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多民族血统分析阿尔茨海默病和帕金森病的 HLA 基因座揭示了由亚型介导的共同适应性免疫反应。

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

机构信息

Department of Neurology and Neurological Sciences, Stanford University, Stanford 94305, CA.

Institut du Cerveau-Paris Brain Institute-ICM, Paris 75013, France.

出版信息

Proc Natl Acad Sci U S A. 2023 Sep 5;120(36):e2302720120. doi: 10.1073/pnas.2302720120. Epub 2023 Aug 29.

DOI:10.1073/pnas.2302720120
PMID:37643212
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10483635/
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 *04 subtypes best accounted for the association, strongest with *04:04 and *04:07, and intermediary with *04:01 and *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 Aβ42. Protective *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 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

摘要

在多民族群体中，我们分析了超过 176000 名帕金森病 (PD) 和阿尔茨海默病 (AD) 患者与对照组个体的人类白细胞抗原 (HLA) 相关性。我们证明这两种疾病在 HLA 基因座上具有相同的保护性关联。HLA 特异性精细映射表明，04 亚型的分层保护作用最能解释这种关联，其中最强的是04:04 和 04:07，其次是04:01 和 04:03。相同的信号与死后大脑中的神经纤维缠结减少有关，与脑脊液中的 tau 水平降低有关，与 Aβ42 增加的相关性较低。保护性04 亚型强烈结合易聚集的 tau PHF6 序列，但只有在赖氨酸 (K311) 乙酰化时才会发生，这是 tau 聚集的一个常见的翻译后修饰，是 tau 聚集的中心。*04 介导的适应性免疫反应降低了 PD 和 AD 的风险，可能是通过针对 tau 起作用，为治疗途径提供了可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/dc46ab67c52d/pnas.2302720120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/7a76fd15d536/pnas.2302720120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/d989c645f1a3/pnas.2302720120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/edead05ba863/pnas.2302720120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/dc46ab67c52d/pnas.2302720120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/7a76fd15d536/pnas.2302720120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/d989c645f1a3/pnas.2302720120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/edead05ba863/pnas.2302720120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46ad/10483635/dc46ab67c52d/pnas.2302720120fig04.jpg

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[1]
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[3]
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[4]
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[10]
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引用本文的文献

[1]
Neuroinflammation distinguishes HLA haplotypes in progressive supranuclear palsy.

medRxiv. 2025-7-21

[2]
Distinct composition of different types of Abeta plaques in the pathogenesis of Alzheimer's disease and the role of neutrophil-derived myeloperoxidase.

Mol Brain. 2025-6-22

[3]
Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.

Nat Genet. 2025-6-18

[4]
MHCII reduction is insufficient to protect mice from alpha-synuclein-induced degeneration and the Parkinson's HLA locus exhibits epigenetic regulation.

Sci Rep. 2025-4-21

[5]
Human leukocyte antigen (HLA) class I and II genetic relationships with brain imaging measures: A systematic review and meta-analysis.

Brain Behav Immun. 2025-8

[6]
MHCII reduction is insufficient to protect mice from alpha-synuclein-induced degeneration and the Parkinson's HLA locus exhibits epigenetic regulation.

bioRxiv. 2025-3-4

[7]
Early detection of Parkinson's disease through multiplex blood and urine biomarkers prior to clinical diagnosis.

NPJ Parkinsons Dis. 2025-2-25

[8]
Interaction of genetic variants and methylation in transcript-level expression regulation in Alzheimer's disease by multi-omics data analysis.

BMC Genomics. 2025-2-20

[9]
Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium.

Alzheimers Dement. 2025-2

[10]
Human Leukocyte Antigen Polymorphism and Blood Biomarker Profiles in Parkinson's Disease: A Pilot Study in a Latvian Cohort.

Biomedicines. 2024-11-27

本文引用的文献

[1]
Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy.

Nature. 2023-3

[2]
Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease.

JAMA. 2023-2-21

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Int J Mol Sci. 2022-6-30

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Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy.

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Brain. 2022-10-21

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Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases.

Prog Neurobiol. 2022-7

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Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels.

Commun Biol. 2022-4-8

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New insights into the genetic etiology of Alzheimer's disease and related dementias.

Nat Genet. 2022-4

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α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity.

Proc Natl Acad Sci U S A. 2022-4-12

[10]
Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy.

Elife. 2022-3-4

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