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

Emmenegger, M.; De Cecco, E.; Hruska-Plochan, M.; Eninger, T.; Schneider, M. M.; Barth, M.; Tantardini, E.; de Rossi, P.; Langston, R. G.; Kaganovich, A.; Gonzalez-Guerra, A.; Avar, M.; Heinzer, D.; Reimann, R.; Häsler, L. M.; Herling, T. W.; Matharu, N. S.; Landeck, N.; Luk, K.; Melki, R.; Kahle, P. J.; Hornemann, S.; Knowles, T. P. J.; Cookson, M. R.; Polymenidou, M.; Jucker, M.; Aguzzi, A.

doi:10.1101/2021.04.25.441302

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bioRxiv · 10.1101/2021.04.25.441302

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

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Abstract

While the initial pathology of Parkinsons disease and other -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 -synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analyzed 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 -synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of -synuclein pathology ex vivo. The overall survival of A53T -synuclein transgenic mice was unaffected by LAG3 depletion and the seeded induction of -synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of -synucleinopathies is not universally valid.

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Emmenegger, M., De Cecco, E., Hruska-Plochan, M., Eninger, T., Schneider, M. M., Barth, M., Tantardini, E., de Rossi, P., Langston, R. G., Kaganovich, A., Gonzalez-Guerra, A., Avar, M., Heinzer, D., Reimann, R., Häsler, L. M., Herling, T. W., Matharu, N. S., Landeck, N., Luk, K., Melki, R., Kahle, P. J., Hornemann, S., Knowles, T. P. J., Cookson, M. R., Polymenidou, M., Jucker, M., Aguzzi, A.. 2021-04-26. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies. https://doi.org/10.1101/2021.04.25.441302

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