LAG3 as a synuclein-fibril receptor

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Xiaobo Mao, Ted and Valina Dawson and colleagues (32 authors, Johns Hopkins, with the immunologists Creg Workman and Dario Vignali, who work on LAG3), Science 353:aah3374, 30 September 2016. Challenge: Marc Emmenegger, Adriano Aguzzi and colleagues (University of Zurich, 29 authors), EMBO Mol Med 13:e14745, July 2021, funded by Swiss and European research grants and the University of Zurich.

What happened

Injecting synuclein fibrils into mice seeds spreading pathology (landmark 51), using lab-made fibrils (landmark 43). The Hopkins team asked how neurons take the fibrils in. LAG3 bound fibrils tightly (dissociation constant 77 nanomolar) but barely bound single synuclein molecules. Binding started uptake, transmission and toxicity; neurons without LAG3 took up less, and mice without it lost fewer dopamine neurons and showed less behavioural deficit after fibril injection. The 2021 paper found no evidence of LAG3 in neurons by several methods, and the fibril binding it confirmed had limited specificity. LAG3 overexpression in human neural cells did not worsen pathology, A53T synuclein mice lived as long without LAG3, and seeding in brain-slice cultures was unchanged by LAG3 knockout. Since then, a January 2025 bioRxiv preprint from the Hopkins group with Workman and Vignali (Yang et al.) reports that deleting LAG3 only in neurons reduces spread and damage in mice and human stem-cell neurons. Europe PMC lists it as still a preprint at this check. Other groups have reported LAG3 involvement in mouse fibril models (Zhang et al., Adv Sci 2023; Kong et al., J Neuroinflammation 2025), and a rival receptor, LRP1, was proposed in 2022.

Why it moved us toward a cure

A receptor would be a drug target for spread, a different approach from antibodies in the fluid between cells (landmark 63).

Outcome

Open and disputed. No LAG3-directed Parkinson's drug was found in a ClinicalTrials.gov search (the LAG3 antibody trials found are in cancer). No correction or retraction of either paper was found; a Science perspective accompanied the 2016 paper.

Sources

• Mao et al., Science 2016, DOI 10.1126/science.aah3374, PMID 27708076 (abstract via Europe PMC)
• Emmenegger et al., EMBO Mol Med 2021, DOI 10.15252/emmm.202114745, PMID 34309222 (abstract and acknowledgements via Europe PMC, PMC8422075)
• Yang et al., bioRxiv 2025, DOI 10.1101/2025.01.03.631221 (preprint)
• Alzforum, "Immune Receptor May Smuggle α-Synuclein into Neurons"
• Not yet verified: the full text of Mao 2016 (summarised from the abstract; funders not read); the Zhang 2023 and Kong 2025 papers (found by title search only); peer-reviewed publication of the Yang preprint.