Evidence map›Paper›PMID 41542562›Full record

ArticlebioRxiv : the preprint server for biology2026

Microglial Lag3 Drives α-Synuclein-induced Neurotoxic Activated (A1) Astrocytes and Neurodegeneration.

Xiuli Yang, Ramhari Kumbhar, Bo Am Seo, Shinwon Ha, Jared T Hinkle, Ning Wang, Shuya Li, Lili Niu, Haiqing Liu, Nicolas Stanciu and 10 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors.

Xiuli YangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ramhari KumbharNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Bo Am SeoNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shinwon HaNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jared T HinkleNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ning WangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shuya LiNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Lili NiuNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Haiqing LiuNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Nicolas StanciuNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Rong ChenNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yasuyoshi KimuraNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Enquan XuNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Fangyi ChengNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sung-Ung KangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mingyao YingDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Han Seok KoNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Valina L DawsonNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ted DawsonNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0002-6459-0893
Xiaobo MaoNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0001-6587-556X

Funding

Medical Scientist Training ProgramT32GM136577 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI ANDREA L COX · 2020 to 2026
$13.4M
Murine Mutagenesis CoreP30NS050274 · NINDS · JOHNS HOPKINS UNIVERSITY · PI KOLODKIN, ALEX L · 2005 to 2020
$10.9M
MIF Nuclease actions in Synuclein DementiasR01AG085688 · NIA · JOHNS HOPKINS UNIVERSITY · PI VALINA L. DAWSON, Ted M. Dawson · 2024 to 2026
$2.4M
Astrocyte NLRP3 inflammasome activation in Parkinson's diseaseF30AG067643 · NIA · JOHNS HOPKINS UNIVERSITY · PI HINKLE, JARED · 2020 to 2022
$153k
NIA NIH HHS F30 AG067643NIA NIH HHS R01 AG085688NIGMS NIH HHS T32 GM136577NINDS NIH HHS P30 NS050274
6 · The paper itself

Abstract

Background: Neuroinflammation and pathologic α-synuclein (α-syn) aggregation cooperate to drive dopaminergic neurodegeneration in Parkinson's disease, but the glial receptors that couple extracellular α-syn to inflammatory cascades remain incompletely defined. Microglia express higher levels of lymphocyte activation gene 3 (Lag3) than neurons, yet the contribution of microglial Lag3 to α-syn recognition, glial crosstalk, and neurodegeneration is unknown. Methods: Biochemical binding assays, live-cell imaging, cytokine profiling, and neuron-microglia-astrocyte co-culture paradigms were used to define Lag3-dependent α-syn preformed fibril (PFF) binding, uptake, and microglial activation. To interrogate in vivo function, microglia-specific Lag3 conditional knockout mice (Lag3 Results: α-syn PFFs bound microglial Lag3 with high specificity and nanomolar affinity and required Lag3 for efficient fibril internalization and induction of proinflammatory cytokines. Microglial Lag3 deficiency markedly blunted α-syn PFF-evoked microglial activation, prevented cytokine-driven conversion of astrocytes into neurotoxic reactive A1 astrocytes, and abolished astrocyte-dependent neuronal death in vitro. In vivo, microglia-specific Lag3 deletion reduced cortical, striatal, and substantia nigra pS129 α-syn pathology, suppressed microgliosis and A1 astrocyte induction, preserved substantia nigra dopaminergic neurons and striatal dopamine transporter/tyrosine hydroxylase expression, and ameliorated α-syn PFF-induced motor deficits. Conclusions: 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.

Identifiers

PMID41542562
PMCPMC12803170

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.