Microglia lrrk2

We report a novel in vitro classification system that tracks microglial activation state and their potential neurotoxicity. Mixed live-cell imaging was used to characterize transition through distinct morphological phenotypes, production of reactive oxygen species (ROS), formation of reactive microglial aggregates, and subsequent cytokine production. Transwell cultures were used to determine microglial migration (control and lipopolysaccharide (LPS) treated) to glutamate pre-stressed or healthy neurons. This two-hit paradigm was developed to model the vast evidence that neurodegenerative conditions, like Parkinson's disease (PD), may stem from the collective impact of multiple environmental stressors...

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of autosomal dominant Parkinson's disease (PD), producing psychiatric and motor symptoms. We conducted this study to explore whether microglial dopaminergic (DAergic) fiber refinement and synaptic pruning are involved in the abnormal behavioral phenotypes of carriers of the LRRK2 G2019S mutation, by employing young and middle-aged PD model mice. The results revealed a characteristic late-onset hyperactivity and a progressive decline in the motor coordination of the LRRK2 G2019S mutation mice...

Parkinson's disease (PD) is one of the most prevalent neurodegenerative aging disorders characterized by motor and non-motor symptoms due to the selective loss of midbrain dopaminergic (DA) neurons. The decreased viability of DA neurons slowly results in the appearance of motor symptoms such as rigidity, bradykinesia, resting tremor, and postural instability. These symptoms largely depend on DA nigrostriatal denervation. Pharmacological and surgical interventions are the main treatment for improving clinical symptoms, but it has not been possible to cure PD...

Parkinson's disease (PD) is mainly driven by dopaminergic neuronal degeneration in the substantia nigra pars compacta accompanied by chronic neuroinflammation. Despite being mainly sporadic, approximately 10% of all cases are defined as heritable forms of PD, with mutations in the leucine-rich repeat kinase ( LRRK2 ) gene being the most frequent known cause of familial PD. MicroRNAs (miRNAs or miRs), including miR-335, are frequently deregulated in neurodegenerative diseases, such as PD. Here, we aimed to dissect the protective role of miR-335 during inflammation and/or neurodegenerative events in experimental models of PD...

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...

Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinson's disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed...

Parkinson's disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons in the substantia nigra (SN). Matrix metalloproteinases-8 (MMP-8), neutrophil collagenase, is a functional player in the progressive pathology of various inflammatory disorders. In this study, we administered an MMP-8 inhibitor (MMP-8i) in Leucine-rich repeat kinase 2 (LRRK2) G2019S transgenic mice, to determine the effects of MMP-8i on PD pathology. We observed a significant increase of ionized calcium- binding adapter molecule 1 (Iba1)-positive activated microglia in the striatum of LRRK2 G2019S mice compared to normal control mice, indicating enhanced neuro-inflammatory responses...

Missense mutations in the leucine-rich repeat kinase-2 (LRRK2) gene represent the most common cause of autosomal dominant Parkinson's disease (PD). In the years LRRK2 has been associated with several organelles and related pathways in cell. However, despite the significant amount of research done in the past decade, the contribution of LRRK2 mutations to PD pathogenesis remains unknown. Growing evidence highlights that LRRK2 controls multiple processes in brain immune cells, microglia and astrocytes, and suggests that deregulated LRRK2 activity in these cells, due to gene mutation, might be directly associated with pathological mechanisms underlying PD...

BACKGROUND: Mouse models have allowed for the direct interrogation of genetic effects on molecular, physiological, and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human- or primate-specific and therefore which components can be faithfully recapitulated in mouse models. RESULTS: We compare conservation of co-expression in 116 independent data sets derived from human, mouse, and non-human primate representing more than 15,000 total samples...

Parkinson's disease-associated kinase LRRK2 has been linked to IFN type II (IFN-γ) response in infections and to dopaminergic neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ remains unclear. In this study, we employed dopaminergic neurons and microglia differentiated from patient-derived induced pluripotent stem cells carrying LRRK2 G2019S, the most common Parkinson's disease-associated mutation. We show that IFN-γ enhances the LRRK2 G2019S-dependent negative regulation of AKT phosphorylation and NFAT activation, thereby increasing neuronal vulnerability to immune challenge...

Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein...

Genetic variation in LRRK2 associates with the susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection. High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells in the immune system. In mouse and human primary macrophages, dendritic cells, and microglia-like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin-mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10, before EEA1 and Rab5 recruitment to early macropinosomes occurs...

The Parkinson's disease-associated gene, LRRK2, is also associated with immune disorders and infectious disease and is expressed in immune subsets. Here, we characterize a platform for interrogating the expression and function of endogenous LRRK2 in authentic human phagocytes using human induced pluripotent stem cell-derived macrophages and microglia. Endogenous LRRK2 is expressed and upregulated by interferon-γ in these cells, including a 187-kDa cleavage product. Using LRRK2 knockout and G2019S isogenic repair lines, we find that LRRK2 is not involved in initial phagocytic uptake of bioparticles but is recruited to LAMP1+ /RAB9+ "maturing" phagosomes, and LRRK2 kinase inhibition enhances its residency at the phagosome...

Neuroinflammation (microglial activation) and subclinical nigrostriatal dysfunction have been reported in subjects at risk of Parkinsonism. Eight non-manifesting carriers (NMCs) of LRRK2 G2019S mutation had 11 C-PK11195 and 18 F-DOPA PET to assess microglial activation and striatal dopamine system integrity, respectively. Comparisons were made with healthy controls. Five LRRK2-NMCs had subclinical reductions of putaminal 18 F-DOPA uptake. Three of them had significantly raised nigral 11 C-PK11195 binding bilaterally...

Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease and many inflammatory processes. Thus, we assessed the role of LRRK2 in the context of endotoxin (lipopolysaccharide, LPS)-induced inflammation of the substantia nigra together with the environmental toxicant, paraquat, that has been implicated in PD. Here we found that LRRK2 ablation prevented the loss of dopaminergic neurons and behavioral deficits (motor) induced by LPS priming followed by paraquat exposure. The LRRK2 ablation also provoked a phenotypic shift in LPS-primed microglia cells...

Leucine-rich repeat kinase 2 ( LRRK2 ) encodes a complex protein that includes kinase and GTPase domains. Genome-wide association studies have identified dominant LRRK2 alleles that predispose their carriers to late-onset idiotypic Parkinson's disease (PD) and also to autoimmune disorders such as Crohn's disease. Considerable evidence indicates that PD initiation and progression involve activation of innate immune functions in microglia, which are brain-resident macrophages. Here we asked whether LRRK2 modifies inflammatory signaling and how this modification might contribute to PD and Crohn's disease...

Parkinson's disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation...

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Several previous studies have linked the Parkinson's disease (PD) gene LRRK2 to the biology of microglia cells. However, the precise ways in which LRRK2 affects microglial function have not been fully resolved. Here, we used the RNA-Sequencing to obtain transcriptomic profiles of LRRK2 wild-type (WT) and knock-out (KO) microglia cells treated with α-synuclein pre-formed fibrils (PFFs) or lipopolysaccharide (LPS) as a general inflammatory insult. We observed that, although α-synuclein PFFs and LPS mediate overlapping gene expression profiles in microglia, there are also distinct responses to each stimulus...

Leucine rich-repeat kinase 2 (LRRK2) is involved in the pathogenesis of Parkinson's disease (PD). LRRK2 has kinase and GTPase activities, and mediates several cell functions, including vesicle trafficking, apoptosis, autophagy, mitochondrial dynamics, and neuroinflammation. G2019S (GS) is the most prevalent mutation of LRRK2. The mutation increases kinase activity, suggesting that this activity is crucial for PD pathogenesis. The activation and inhibition of LRRK2 kinase increases and reduces the levels of proinflammatory cytokines, respectively suggesting that the role of LRRK2 in neuroinflammation is critical for the pathology of PD...