LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies

Kim, Changyoun; Beilina, A; Smith, Nathan J.; Li, Yan; Kim, Minhyung; Kumaran, R. Ileng; Kaganovich, Alice; Mamais, Adamantios; Adame, Anthony; Iba, Michiyo; Kwon, Somin; Lee, Won Jae; Shin, Soo Jean; Rissman, Robert A.; You, Sungyong; Lee, Seung-Jae; Singleton, Andrew B.; Cookson, Mark; Masliah, Eliezer

doi:10.1126/scitranslmed.aay0399

Cited by 61 publications

(52 citation statements)

References 95 publications

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“…Chronic inflammation is a well-established feature of neurodegenerative diseases [27], which can contribute to dopaminergic neuronal loss [28]. Kim et al observed that neuron-released αsynuclein promotes activation of LRRK2 in Lipopolysaccharide (LPS) induced rodent microglia, triggering proinflammatory cascade through release of cytokines [29,30]. Increased LRRK2 mRNA levels accompanied with increased striatal α-synuclein deposits in postmortem PD patients in a previous study [31] suggests that LRRK2 and SNCA might be co-regulated.…”

Section: Discussionmentioning

confidence: 98%

Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

Pande

Huang

Teeple

et al. 2021

Preprint

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Understanding disease biology at a cellular level from disease specific tissues is imperative for effective drug development for complex neurodegenerative diseases. We profiled 87,086 nuclei from putamen tissue of healthy controls, Parkinson's Disease (PD), and Multiple System Atrophy (MSA) subjects to construct a comprehensive single cell atlas. Although both PD and MSA are manifestations of alpha-synuclein protein aggregation, we observed that both the diseases have distinct cell-type specific changes. We see a possible expansion and activation of microglia and astrocytes in PD compared to MSA and controls. Contrary to PD microglia, we found absence of upregulated unfolded protein response in MSA microglia compared to controls. Differentially expressed genes in major cell types are enriched for genes associated with PD-GWAS loci. We found altered expression of major neurodegeneration associated genes, SNCA, MAPT, LRRK2, and APP, at cell-type resolution. We also identified disease associated gene modules using a network biology approach. Overall, this study creates an interactive atlas from synucleinopathies and provides major cell-type specific disease insights.

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Section: Discussionmentioning

confidence: 98%

Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

Pande

Huang

Teeple

et al. 2021

Preprint

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“…This was demonstrated via increased levels of Drp1, a mitochondrial fission marker, CD68, a microglia activation marker and TNF-α in LRRK2 mutant mice ( 122 ). Furthermore, inhibition of LRRK2 has been shown to attenuate microglial inflammatory response to TLR4 stimulation ( 123 ), and activation of microglia by extracellular α-syn ( 124 , 125 ).…”

Section: Microglia and Their Role In Parkinson's Diseasementioning

confidence: 99%

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

et al. 2021

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Parkinson's disease (PD), the second most common neurodegenerative disease, is characterised by the motor symptoms of bradykinesia, rigidity and resting tremor and non-motor symptoms of sleep disturbances, constipation, and depression. Pathological hallmarks include neuroinflammation, degeneration of dopaminergic neurons in the substantia nigra pars compacta, and accumulation of misfolded α-synuclein proteins as intra-cytoplasmic Lewy bodies and neurites. Microglia and astrocytes are essential to maintaining homeostasis within the central nervous system (CNS), including providing protection through the process of gliosis. However, dysregulation of glial cells results in disruption of homeostasis leading to a chronic pro-inflammatory, deleterious environment, implicated in numerous CNS diseases. Recent evidence has demonstrated a role for peripheral immune cells, in particular T lymphocytes in the pathogenesis of PD. These cells infiltrate the CNS, and accumulate in the substantia nigra, where they secrete pro-inflammatory cytokines, stimulate surrounding immune cells, and induce dopaminergic neuronal cell death. Indeed, a greater understanding of the integrated network of communication that exists between glial cells and peripheral immune cells may increase our understanding of disease pathogenesis and hence provide novel therapeutic approaches.

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“…Recently, Masliah et al characterized a novel neuroinflammation cascade dependent on LRRK2-nuclear factor of activated T cells, cytoplasmic 2 (LRRK2-NFATc2) in microglia activated by neuron-released α-synuclein 15 ( Figure 1 ). In this study, the level of LRRK2 phosphorylation and activity increased in mouse primary microglia with extracellular α-synuclein treatment.…”

mentioning

confidence: 99%

LRRK2-NFATc2 Pathway Associated with Neuroinflammation May Be a Potential Therapeutic Target for Parkinson’s Disease

Wang¹,

Zhang²,

Chen³

et al. 2021

JIR

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Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD). However, the molecular mechanisms involved in extracellular α‑synuclein-induced proinflammatory microglial responses through Toll-like receptor 2 (TLR2) are unclear. Leucine-rich repeat kinase 2 (LRRK2) is a serine/threonine kinase, and its mutations are closely related to autosomal dominant PD. Recently, Masliah et al characterized a novel-specific neuroinflammation cascade dependent on LRRK2-NFATc2 in microglia activated by neuron-released α-synuclein. LRRK2 selectively phosphorylated and induced nuclear translocation of NFATc2 to activate a neuroinflammation cascade. In this cascade, LRRK2 kinase was activated by neuron-released α-synuclein in microglia via TLR2. Further, NFATc2, as a kinase substrate for LRRK2, was directly phosphorylated, which accelerated nuclear translocation of NFATc2, where cytokine/chemokine gene expression including TNF-α and IL-6 is regulated by NFATc2 transcriptional activity, resulting in a neurotoxic inflammatory environment. Moreover, an abnormal increase of NFATc2 in nuclear was observed in the brains of patients and a mouse model of PD. Additionally, the administration of an LRRK2 inhibitor could ameliorate neuroinflammation, prevent neuronal loss, and improve motor function. Therefore, modulation of LRKK2-NFATc2 signaling cascade might be a potential therapeutic target for the treatment of PD.

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LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies

Cited by 61 publications

References 95 publications

Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?

LRRK2-NFATc2 Pathway Associated with Neuroinflammation May Be a Potential Therapeutic Target for Parkinson’s Disease

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