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LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies


Abstract

While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.

Abstract

While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Medicine
Uncontrolled Keywords:Molecular Medicine
Language:English
Date:26 July 2021
Deposited On:23 Aug 2021 12:54
Last Modified:01 Oct 2021 19:52
Publisher:Wiley Open Access
ISSN:1757-4676
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/emmm.202114745
PubMed ID:34309222
Project Information:
  • : FunderSPHN
  • : Grant ID2017DRI17
  • : Project TitlePopulation-wide screens of the human immune repertoire
  • : Project Websitehttps://sphn.ch/de/projects/driver-projects/
  • : FunderNOMIS Foundation
  • : Grant ID
  • : Project TitleDistinguished Scientist Award
  • : Project Websitehttps://nomisfoundation.ch/people/adriano-aguzzi/
  • : FunderH2020
  • : Grant ID670958
  • : Project TitleFunction and malfunction of the prion protein
  • : Project Websitehttps://cordis.europa.eu/project/id/670958
  • : FunderSNSF
  • : Grant ID310030_192650
  • : Project TitleExploring the molecular basis of disease heterogeneity in TDP-43 proteinopathies
  • : FunderH2020
  • : Grant ID674979
  • : Project TitleTRANSPORT OF SOFT MATTER AT THE NANOSCALE
  • : FunderSNSF
  • : Grant ID51NF40-182880
  • : Project TitleNCCR RNA & disease: The role of RNA biology in disease mechanisms (phase II)

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