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

While the initial pathology of Parkinson's 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.