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Cited by 93Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsGlycosylation and Glycoproteins Research

Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease

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Rathore, Nisha, Ramani, Sree Ranjani, Pantua, Homer, Payandeh, Jian, Bhangale, Tushar, Wuster, Arthur, Kapoor, Manav, Sun, Yonglian +7 more·2018·PLOS Genetics
DOI 10.1371/journal.pgen.1007427PMC PMC6235402

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Abstract

Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer's disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer's disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.

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  • The analyses nominate alternative candidates at three AD risk loci: CR2 at 1q32.2, PILRA at 7q22.1, and PRSS8 at 16p11.2.

    “Our analyses also nominate alternative candidates at three AD risk loci. First, the association at 1q32.2 has been linked to CR153–55, but we observed a colocalized association for both CR1 and CR2 levels with AD risk (Supp. Fig. 23).”

    From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [58]

    The Results section identifies a PILRA variant associated with protection from Alzheimer’s disease, supporting PILRA as a candidate at one AD risk locus. It calls that locus 7q21, not 7q22.1, and does not support the claim’s CR2 or PRSS8 candidates. No page number is available in our copy. (LLM, conf=0.88)

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Authors
Rathore, N., Ramani, S. R., Pantua, H., Payandeh, J., Bhangale, T., Wuster, A., Kapoor, M., Sun, Y., Kapadia, S. B., Gonzalez, L., Zarrin, A. A., Goate, A., Hansen, D. V., Behrens, T. W., & Graham, R. R.
Affiliations
  • Genentech (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Behrens, Timothy W.
  • Graham, Robert R.
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2018-11-02
Volume
14
Issue
11
Pages
e1007427
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1007427
PMC
PMC6235402
OpenAlex
W2949342392
Cited by
93
References
8
Citations by year
2026: 11 · 2025: 14 · 2024: 13 · 2023: 3 · 2022: 15 · 2021: 16 · 2020: 9 · 2019: 11 · 2018: 1
FWCI
6.15
Type
journal article
Language
en
Update notices
new_version (2018-11-14)
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (1s10od018522-01)
  • Genentech
  • National Institute on Aging (U24AG021886)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
Keywords
Alzheimer's disease risk, sialic acid binding, inhibitory receptors, microglia, HSV-1 infection, glycoprotein B, complement C4A, macrophages, genetic susceptibility loci
MeSH terms
Alzheimer Disease, Animals, Humans, Ligands, Membrane Glycoproteins, Models, Biological, Molecular Conformation, Protein Binding, Receptors, Immunologic, Structure-Activity Relationship, Genetic Variation, Amino Acid Substitution, Quantitative Trait Loci, Mice, Genetic Loci

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