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

Marc Emmenegger (1) , Elena de Cecco (1) , Marian Hruska‐plochan (1) , Timo Eninger (2) , Matthias M Schneider (3) , Melanie Barth (2) , Elena Tantardini (1) , Pierre de Rossi (1) , Mehtap Bacioglu (2) , Rebekah G Langston (4) , Alice Kaganovich (4) , Nora Bengoa‐vergniory (5) , Andrès Gonzalez‐guerra (1) , Merve Avar (1) , Daniel Heinzer (1) , Regina Reimann (1) , Lisa M Häsler (2) , Therese W Herling (3) , Naunehal S Matharu (3) , Natalie Landeck (4) , Kelvin Luk (6) , Ronald Melki (7) , Philipp J Kahle (8, 2) , Simone Hornemann (1) , Tuomas P J Knowles (8) , Mark R Cookson (4) , Magdalini Polymenidou (1) , Mathias Jucker (2) , Adriano Aguzzi (1)

1 UZH - Universität Zürich [Zürich] = University of Zurich
2 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
3 CAM - University of Cambridge [UK]
4 NIH - National Institutes of Health [Bethesda, MD, USA]
5 University of Oxford
6 Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
7 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
8 University of Tübingen

While the initial pathology of Parkinson's disease and other αsynucleinopathies 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 αsynuclein 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 αsynuclein 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.

Mots clés: LAG3; neurodegeneration; prionoids; α-synuclein

Domaines: Neurosciences [q-bio.NC]

Marc Emmenegger, Elena de Cecco, Marian Hruska‐plochan, Timo Eninger, Matthias M Schneider, et al.. LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies. EMBO Molecular Medicine, 2021, pp.e14745. ⟨10.15252/emmm.202114745⟩. ⟨cea-03301324⟩