Microglial Lag3 Drives α-Synuclein–induced Neurotoxic Activated (A1) Astrocytes and Neurodegeneration
This study identifies microglial Lag3 as a key receptor linking extracellular α-syn PFF recognition to inflammatory amplification, neurotoxic reactive A1 astrocyte conversion, and dopaminergic neurodegeneration. Together with prior work on neuronal Lag3, these findings support a cell-type-specific dual-axis model in which neuronal Lag3 mediates α-syn propagation while microglial Lag3 drives glia-dependent neurotoxicity, positioning Lag3 as a promising precision therapeutic target in α-synucleinopathies.
Authors
- Ramhari Kumbhar (ORCID: https://orcid.org/0000-0002-8975-2502)
- Sung-Ung Kang (ORCID: https://orcid.org/0000-0002-8393-2588)
- Valina L. Dawson (ORCID: https://orcid.org/0000-0002-2915-3970)
- Han Seok Ko
- Enquan Xu (ORCID: https://orcid.org/0000-0003-3463-0337)
- Xiaobo Mao (ORCID: https://orcid.org/0000-0001-6587-556X)
- Yasuyoshi Kimura (ORCID: https://orcid.org/0000-0001-9147-8058)
- S. -H. Li
- Bo Am Seo (ORCID: https://orcid.org/0000-0001-9507-2362)
- Mingyao Ying (ORCID: https://orcid.org/0000-0002-6215-4959)
- Jared T. Hinkle (ORCID: https://orcid.org/0000-0001-6770-3067)
- Nicolas Stanciu (ORCID: https://orcid.org/0009-0001-7677-8455)
- Ning Wang (ORCID: https://orcid.org/0000-0002-3410-8509)
- Xiuli Yang
- F. C. Cheng
- Ted Dawson
- Haiqing Liu
- Rong Chen
- Lili Niu
- Shinwon Ha
Institutions
- Kennedy Krieger Institute (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-06
- DOI
- https://doi.org/10.64898/2026.01.06.697996
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Robert J. and Claire Pasarow Foundation
- Adrienne Helis Malvin Medical Research Foundation
- Johns Hopkins University
- National Institutes of Health
- National Institute on Aging
- National Institute of General Medical Sciences