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1
Civiero, Laura, and Luigi Bubacco. "Human leucine-rich repeat kinase 1 and 2: intersecting or unrelated functions?" Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1095–101. http://dx.doi.org/10.1042/bst20120123.
Повний текст джерелаАнотація:
Mutations in LRRK2 (leucine-rich repeat kinase 2) are associated with both familial and sporadic PD (Parkinson's disease). LRRK1 (leucine-rich repeat kinase 1) shares a similar domain structure with LRRK2, but it is not linked to PD. LRRK proteins belong to a gene family known as ROCO, which codes for large proteins with several domains. All ROCO proteins have a ROC (Ras of complex proteins) GTPase domain followed by a domain of unknown function [COR (C-terminal of ROC)]. LRRK2, LRRK1 and other ROCO proteins also possess a kinase domain. To date, the function of LRRK1 and both the physiological and the pathological roles of LRRK2 are only beginning to unfold. The comparative analysis of these two proteins is a strategy to single out the specific properties of LRRKs to understand their cellular physiology. This comparison is the starting point to unravel the pathways that may lead to PD and eventually to develop therapeutic strategies for its treatment. In the present review, we discuss recently published results on LRRK2 and its paralogue LRRK1 concerning their evolutionary significance, biochemical properties and potential functional roles.
2
Langston, Rebekah G., Iakov N. Rudenko, and Mark R. Cookson. "The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research." Biochemical Journal 473, no. 3 (January 25, 2016): 221–32. http://dx.doi.org/10.1042/bj20150985.
Повний текст джерелаАнотація:
In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.
3
Suzzi, Stefano, Reiner Ahrendt, Stefan Hans, Svetlana A. Semenova, Avinash Chekuru, Paul Wirsching, Volker Kroehne, et al. "Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain." PLOS Genetics 17, no. 9 (September 13, 2021): e1009794. http://dx.doi.org/10.1371/journal.pgen.1009794.
Повний текст джерелаАнотація:
LRRK2 gain-of-function is considered a major cause of Parkinson’s disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafish lrrk2 locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast to lrrk2, the paralog gene lrrk1 is virtually not expressed in the brain of both wild-type and mzLrrk2 fish at different developmental stages. Notably, we found reduced catecholaminergic neurons, the main target of PD, in specific cell populations in the brains of mzLrrk2 larvae, but not adult fish. Strikingly, age-dependent accumulation of monoamine oxidase (MAO)-dependent catabolic signatures within mzLrrk2 brains revealed a previously undescribed interaction between LRRK2 and MAO biological activities. Our results highlight mzLrrk2 zebrafish as a tractable tool to study LRRK2 loss-of-function in vivo, and suggest a link between LRRK2 and MAO, potentially of relevance in the prodromic stages of PD.
4
Chung, Sun-Ku, and Seo-Young Lee. "Advances in Gene Therapy Techniques to Treat LRRK2 Gene Mutation." Biomolecules 12, no. 12 (December 5, 2022): 1814. http://dx.doi.org/10.3390/biom12121814.
Повний текст джерелаАнотація:
Leucine-rich repeat kinase 2 (LRRK2) gene mutation is an autosomal dominant mutation associated with Parkinson’s disease (PD). Among LRRK2 gene mutations, the LRRK2 G2019S mutation is frequently involved in PD onset. Currently, diverse gene correction tools such as zinc finger nucleases (ZFNs), helper-dependent adenoviral vector (HDAdV), the bacterial artificial chromosome-based homologous recombination (BAC-based HR) system, and CRISPR/Cas9-homology-directed repair (HDR) or adenine base editor (ABE) are used in genome editing. Gene correction of the LRRK2 G2019S mutation has been applied whenever new gene therapy tools emerge, being mainly applied to induced pluripotent stem cells (LRRK2 G2019S-mutant iPSCs). Here, we comprehensively introduce the principles and methods of each programmable nuclease such as ZFN, CRISPR/Cas9-HDR or ABE applied to LRRK2 G2019S, as well as those of HDAdV or BAC-based HR systems used as nonprogrammable nuclease systems.
5
Maset, Andrea, Marco Albanesi, Antonio di Soccio, Martina Canova, Marco dal Maschio, and Claudia Lodovichi. "Aberrant Patterns of Sensory-Evoked Activity in the Olfactory Bulb of LRRK2 Knockout Mice." Cells 10, no. 11 (November 17, 2021): 3212. http://dx.doi.org/10.3390/cells10113212.
Повний текст джерелаАнотація:
The LRRK2 gene is the major genetic determinant of familiar Parkinson’s disease (PD). Leucine-rich repeat kinase 2 (LRRK2) is a multidomain protein involved in several intracellular signaling pathways. A wealth of evidence indicates that LRRK2 is enriched at the presynaptic compartment where it regulates vesicle trafficking and neurotransmitter release. However, whether the role of LRRK2 affects neuronal networks dynamic at systems level remains unknown. Addressing this question is critical to unravel the impact of LRRK2 on brain function. Here, combining behavioral tests, electrophysiological recordings, and functional imaging, we investigated neuronal network dynamics, in vivo, in the olfactory bulb of mice carrying a null mutation in LRRK2 gene (LRRK2 knockout, LRRK2 KO, mice). We found that LRRK2 KO mice exhibit olfactory behavioral deficits. At the circuit level, the lack of LRRK2 expression results in altered gamma rhythms and odorant-evoked activity with significant impairments, while the spontaneous activity exhibited limited alterations. Overall, our data in the olfactory bulb suggest that the multifaced role of LRRK2 has a strong impact at system level when the network is engaged in active sensory processing.
6
Xiong, Yulan, Valina L. Dawson, and Ted M. Dawson. "LRRK2 GTPase dysfunction in the pathogenesis of Parkinson's disease." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1074–79. http://dx.doi.org/10.1042/bst20120093.
Повний текст джерелаАнотація:
Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene are the most frequent genetic cause of PD (Parkinson's disease), and these mutations play important roles in sporadic PD. The LRRK2 protein contains GTPase and kinase domains and several protein–protein interaction domains. The kinase and GTPase activity of LRRK2 seem to be important in regulating LRRK2-dependent cellular signalling pathways. LRRK2's GTPase and kinase domains may reciprocally regulate each other to direct LRRK2's ultimate function. Although most LRRK2 investigations are centred on LRRK2's kinase activity, the present review focuses on the function of LRRK2's GTPase activity in LRRK2 physiology and pathophysiology.
7
Filippini, Alice, Massimo Gennarelli, and Isabella Russo. "Leucine-rich repeat kinase 2-related functions in GLIA: an update of the last years." Biochemical Society Transactions 49, no. 3 (May 7, 2021): 1375–84. http://dx.doi.org/10.1042/bst20201092.
Повний текст джерелаАнотація:
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. In this brief review, we recapitulate and update the last LRRK2 functions dissected in microglia and astrocytes. Moreover, we discuss how dysfunctions of LRRK2-related pathways may impact glia physiology and their cross-talk with neurons, thus leading to neurodegeneration and progression of PD.
8
Ikezu, Tsuneya, Lacin Koro, Benjamin Wolozin, Francis A. Farraye, Audrey J. Strongosky, and Zbigniew K. Wszolek. "Crohn’s and Parkinson’s Disease-Associated LRRK2 Mutations Alter Type II Interferon Responses in Human CD14+ Blood Monocytes Ex Vivo." Journal of Neuroimmune Pharmacology 15, no. 4 (March 16, 2020): 794–800. http://dx.doi.org/10.1007/s11481-020-09909-8.
Повний текст джерелаАнотація:
AbstractThe Leucine Rich Repeat Kinase 2 (LRRK2) is one of causative genes of familial Parkinson’s disease (PD). The M2397T polymorphism in LRRK2 is genetically associated with sporadic Crohn’s disease (CD). LRRK2 is expressed in human CD14+ monocytes, induced by interferon-γ (IFN-γ) and suppresses inflammatory activation. We hypothesize that IFN-γ-induced LRRK2 and inflammatory gene expression is altered by LRRK2 genetic polymorphism found in CD and PD cases. A total of 46 CD and 51 control cases, and 16 PD cases and 16 PD-linked LRRK2 mutation cases were recruited. Live human CD14+ monocytes were isolated from donors for ex vivo IFN-γ stimulation and gene expression analysis. IFN-γ potently enhanced TNFA, IL12, HLADRA1 and LRRK2 expression, which was suppressed by FK506, a calcineurin-specific inhibitor, but further enhanced by LRRK2-specific kinase inhibitor (GSK2578215A). The 2397-M/M CD risk allele enhanced IFN-γ responses of CD14+ cells in CD but not in control group. CD14+ monocytes from G2019S and R1441C LRRK2 mutated PD cases and carriers show no changes in IFN-γ responses for TNFA or IL12, reduced response for HLADRA1, and enhanced responses for LRRK2 in FK506-sensitive manner. These data demonstrate that CD-associated LRRK2 mutations are significant modifiers of innate immune response in CD14+ monocytes, and PD-associated LRRK2 mutation may contribute to reduced antigen presentation response.
9
Iseki, Tatou, Yuzuru Imai, and Nobutaka Hattori. "Is Glial Dysfunction the Key Pathogenesis of LRRK2-Linked Parkinson’s Disease?" Biomolecules 13, no. 1 (January 15, 2023): 178. http://dx.doi.org/10.3390/biom13010178.
Повний текст джерелаАнотація:
Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD.
10
Pérez-Carrión, María Dolores, Inmaculada Posadas, Javier Solera, and Valentín Ceña. "LRRK2 and Proteostasis in Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 12 (June 18, 2022): 6808. http://dx.doi.org/10.3390/ijms23126808.
Повний текст джерелаАнотація:
Parkinson’s disease is a neurodegenerative condition initially characterized by the presence of tremor, muscle stiffness and impaired balance, with the deposition of insoluble protein aggregates in Lewy’s Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson’s disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson’s disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of α-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson’s disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin–proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson’s disease through the regulation of LRRK2, using small molecules or LRRK2 silencing.
11
Onishi, Keisuke, Runyi Tian, Bo Feng, Yiqiong Liu, Junkai Wang, Yinan Li, and Yimin Zou. "LRRK2 mediates axon development by regulating Frizzled3 phosphorylation and growth cone–growth cone communication." Proceedings of the National Academy of Sciences 117, no. 30 (July 8, 2020): 18037–48. http://dx.doi.org/10.1073/pnas.1921878117.
Повний текст джерелаАнотація:
Axon–axon interactions are essential for axon guidance during nervous system wiring. However, it is unknown whether and how the growth cones communicate with each other while sensing and responding to guidance cues. We found that the Parkinson’s disease gene, leucine-rich repeat kinase 2 (LRRK2), has an unexpected role in growth cone–growth cone communication. The LRRK2 protein acts as a scaffold and induces Frizzled3 hyperphosphorylation indirectly by recruiting other kinases and also directly phosphorylates Frizzled3 on threonine 598 (T598). InLRRK1orLRRK2single knockout,LRRK1/2double knockout, andLRRK2 G2019Sknockin, the postcrossing spinal cord commissural axons are disorganized and showed anterior–posterior guidance errors after midline crossing. Growth cones from eitherLRRK2knockout orG2019Sknockin mice showed altered interactions, suggesting impaired communication. Intercellular interaction between Frizzled3 and Vangl2 is essential for planar cell polarity signaling. We show here that this interaction is regulated by phosphorylation of Frizzled3 at T598 and can be regulated by LRRK2 in a kinase activity-dependent way. In theLRRK1/2double knockout orLRRK2 G2019Sknockin, the dopaminergic axon bundle in the midbrain was significantly widened and appeared disorganized, showing aberrant posterior-directed growth. Our findings demonstrate that LRRK2 regulates growth cone–growth cone communication in axon guidance and that both loss-of-function mutation and a gain-of-function mutation (G2019S)cause axon guidance defects in development.
12
Santos-Rebouças, Cíntia Barros, Cláudia Bueno Abdalla, Paloma Águia Martins, Fábio José Rodrigues Baldi, Jussara Mendonça Santos, Luciana Branco Motta, Margarete Borges de Borges, et al. "LRRK2p.G2019S Mutation Is Not Common among Alzheimer’s Disease Patients in Brazil." Disease Markers 27, no. 1 (2009): 13–16. http://dx.doi.org/10.1155/2009/298182.
Повний текст джерелаАнотація:
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have emerged as a potential common cause for both sporadic and familial Parkinson’s Disease (PD) in different populations. The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD. The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer’s Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis. We screened the most common LRRK2 mutation (p.G2019S) in a series of 180 consecutive patients clinically diagnosed with Alzheimer Disease (AD). We identified the p.G2019S in one AD patient with no PD signs, indicating that this mutation is not a common etiological factor for AD in our population (0.5%), corroborating recent data found in Norwegian, North American, Chinese and Italian populations. Nevertheless, these observations together with new information about the Lrrk2 critical multifunctionality do not rule out the possible influence of other variants within LRRK2 in AD, so that other screenings focusing in the whole extension of the LRRK2 using larger sized confirmed AD sample are urgently needed.
13
Ogata, Jun, Kentaro Hirao, Kenya Nishioka, Arisa Hayashida, Yuanzhe Li, Hiroyo Yoshino, Soichiro Shimizu, Nobutaka Hattori, and Yuzuru Imai. "A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels." International Journal of Molecular Sciences 22, no. 7 (April 2, 2021): 3708. http://dx.doi.org/10.3390/ijms22073708.
Повний текст джерелаАнотація:
Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.
14
Liu, Weiwei, Xia’nan Liu, Yu Li, Junjie Zhao, Zhenshan Liu, Zhuqin Hu, Ying Wang, et al. "LRRK2 promotes the activation of NLRC4 inflammasome during Salmonella Typhimurium infection." Journal of Experimental Medicine 214, no. 10 (August 18, 2017): 3051–66. http://dx.doi.org/10.1084/jem.20170014.
Повний текст джерелаАнотація:
Although genetic polymorphisms in the LRRK2 gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 in the activation of the NLRC4 inflammasome during host defense against Salmonella enteric serovar Typhimurium infection. LRRK2 deficiency reduced caspase-1 activation and IL-1β secretion in response to NLRC4 inflammasome activators in macrophages. Lrrk2−/− mice exhibited impaired clearance of pathogens after acute S. Typhimurium infection. Mechanistically, LRRK2 formed a complex with NLRC4 in the macrophages, and the formation of the LRRK2–NLRC4 complex led to the phosphorylation of NLRC4 at Ser533. Importantly, the kinase activity of LRRK2 is required for optimal NLRC4 inflammasome activation. Collectively, our study reveals an important role for LRRK2 in the host defense by promoting NLRC4 inflammasome activation.
15
Guaitoli, Giambattista, Bernd K. Gilsbach, Francesco Raimondi, and Christian Johannes Gloeckner. "First model of dimeric LRRK2: the challenge of unrevealing the structure of a multidomain Parkinson's-associated protein." Biochemical Society Transactions 44, no. 6 (December 2, 2016): 1635–41. http://dx.doi.org/10.1042/bst20160226.
Повний текст джерелаАнотація:
Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of Mendelian forms of Parkinson's disease, among autosomal dominant cases. Its gene product, LRRK2, is a large multidomain protein that belongs to the Roco protein family exhibiting GTPase and kinase activity, with the latter activity increased by pathogenic mutations. To allow rational drug design against LRRK2 and to understand the cross-regulation of the G- and the kinase domain at a molecular level, it is key to solve the three-dimensional structure of the protein. We review here our recent successful approach to build the first structural model of dimeric LRRK2 by an integrative modeling approach.
16
Ito, Genta, and Takeshi Iwatsubo. "Re-examination of the dimerization state of leucine-rich repeat kinase 2: predominance of the monomeric form." Biochemical Journal 441, no. 3 (January 16, 2012): 987–98. http://dx.doi.org/10.1042/bj20111215.
Повний текст джерелаАнотація:
Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene have been identified in PARK8, a major form of autosomal-dominantly inherited familial Parkinson's disease, although the biochemical properties of LRRK2 are not fully understood. It has been proposed that LRRK2 predominantly exists as a homodimer on the basis of the observation that LRRK2, with a theoretical molecular mass of 280 kDa, migrates at 600 kDa (p600 LRRK2) on native polyacrylamide gels. In the present study, we biochemically re-examined the nature of p600 LRRK2 and found that p600 LRRK2 was fractionated with a single peak at ~272 kDa by ultracentrifugation on a glycerol gradient. In addition, p600 LRRK2 behaved similarly to monomeric proteins upon two-dimensional electrophoretic separation. These results suggested a monomeric composition of p600 LRRK2 within cells. The p600 LRRK2 exhibited kinase activity as well as GTP-binding activity, and forced dimerization of LRRK2 neither upregulated its kinase activity nor altered its subcellular localization. Collectively, we conclude that the monomer form of LRRK2 is predominant within cells, and that dimerization is dispensable for its enzymatic activity.
17
Jeong, Ga Ram, and Byoung Dae Lee. "Pathological Functions of LRRK2 in Parkinson’s Disease." Cells 9, no. 12 (November 30, 2020): 2565. http://dx.doi.org/10.3390/cells9122565.
Повний текст джерелаАнотація:
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are common genetic risk factors for both familial and sporadic Parkinson’s disease (PD). Pathogenic mutations in LRRK2 have been shown to induce changes in its activity, and abnormal increase in LRRK2 kinase activity is thought to contribute to PD pathology. The precise molecular mechanisms underlying LRRK2-associated PD pathology are far from clear, however the identification of LRRK2 substrates and the elucidation of cellular pathways involved suggest a role of LRRK2 in microtubule dynamics, vesicular trafficking, and synaptic transmission. Moreover, LRRK2 is associated with pathologies of α-synuclein, a major component of Lewy bodies (LBs). Evidence from various cellular and animal models supports a role of LRRK2 in the regulation of aggregation and propagation of α-synuclein. Here, we summarize our current understanding of how pathogenic mutations dysregulate LRRK2 and discuss the possible mechanisms leading to neurodegeneration.
18
Lee, Seo-Young, and Sun-Ku Chung. "Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One-Step Strategy to Overcome Stem Cell-Based Gene Therapy Limitations." Stem Cells International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/2725670.
Повний текст джерелаАнотація:
The recent advent of induced pluripotent stem cells (iPSCs) and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. In addition, as genetic etiology of Parkinson’s disease, it has been well known that induced neural stem cells (iNSCs) were progressively depleted by LRRK2 gene mutation, LRRK2 (G2019S). Thus, to maintain the induced NSCs directly derived from PD patient cells harboring LRRK2 (G2019S), it would be ideal to simultaneously treat the LRRK2 (G2019S) fibroblast during the process of TD. Therefore, simultaneous reprogramming (or TD) and gene therapy would provide the solution for therapeutic limitation caused by vulnerability of reprogramming or TD, in addition to being suitable for general application to the generation of autologous cell-therapy products for patients with genetic defects, thereby obviating the need for the arduous processes currently required.
19
Lewis, Patrick A., and Dario R. Alessi. "Deciphering the function of leucine-rich repeat kinase 2 and targeting its dysfunction in disease1." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1039–41. http://dx.doi.org/10.1042/bst20120178.
Повний текст джерелаАнотація:
LRRK2 (leucine-rich repeat kinase 2) is a gene of unknown function that has been linked to a number a human diseases, including PD (Parkinson's disease), IBD (inflammatory bowel disease), leprosy and cancer. The papers from the LRRK2: Function and Dysfunction meeting in this issue of Biochemical Society Transactions explore our growing knowledge of LRRK2's normal function, the role that it plays in disease and emerging strategies to exploit LRRK2 as a therapeutic target.
20
Levy, Daniel R., Atul Udgata, Panagiotis Tourlomousis, Martyn F. Symmons, Lee J. Hopkins, Clare E. Bryant, and Nicholas J. Gay. "The Parkinson's disease–associated kinase LRRK2 regulates genes required for cell adhesion, polarization, and chemotaxis in activated murine macrophages." Journal of Biological Chemistry 295, no. 31 (February 28, 2020): 10857–67. http://dx.doi.org/10.1074/jbc.ra119.011842.
Повний текст джерелаАнотація:
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. We used RNA-Seq–based high-resolution transcriptomics to compare gene expression in activated primary macrophages derived from WT and Lrrk2 knockout mice. Remarkably, expression of a single gene, Rap guanine nucleotide exchange factor 3 (Rapgef3), was strongly up-regulated in the absence of LRRK2 and down-regulated in its presence. We observed similar regulation of Rapgef3 expression in cells treated with a highly specific inhibitor of LRRK2 protein kinase activity. Rapgef3 encodes an exchange protein, activated by cAMP 1 (EPAC-1), a guanine nucleotide exchange factor that activates the small GTPase Rap-1. Rap-1 mediates cell adhesion, polarization, and directional motility, and our results indicate that LRRK2 modulates chemotaxis of microglia and macrophages. Dominant PD-associated LRRK2 alleles may suppress EPAC-1 activity, further restricting motility and preventing efficient migration of microglia to sites of neuronal damage. Functional analysis in vivo in a subclinical infection model also indicated that Lrrk2 subtly modifies the inflammatory response. These results indicate that LRRK2 modulates the expression of genes involved in murine immune cell chemotaxis.
21
Thakur, Gunjan, Vikas Kumar, Keun Woo Lee, and Chungkil Won. "Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade." Genes 13, no. 8 (August 11, 2022): 1426. http://dx.doi.org/10.3390/genes13081426.
Повний текст джерелаАнотація:
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.
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Liou, Geou-Yarh, and Kathleen A. Gallo. "New biochemical approaches towards understanding the Parkinson's disease-associated kinase, LRRK2." Biochemical Journal 424, no. 1 (October 23, 2009): e1-e3. http://dx.doi.org/10.1042/bj20091540.
Повний текст джерелаАнотація:
Some 5 years ago, it was first discovered that mutations in the gene encoding LRRK2 (leucine-rich repeat protein kinase 2) are tightly linked with a subset of familial PD (Parkinson's disease). Before this genetic association, LRRK2 had never been investigated biochemically. Now it is of utmost importance to establish whether LRRK2 is a bona fide kinase in vitro and in vivo and to understand how mutations of LRRK2 lead to the specific loss of dopaminergic neurons in the substantia nigra to cause PD. In spite of tremendous efforts in the research community, there is no consensus with regard to the magnitude of the enzymatic activity of LRRK2 mutant forms that segregate with PD owing, in part, to the lack of a highly sensitive kinase assay system, and it is still unclear whether an abnormal increase in kinase activity is responsible for LRRK2-associated PD. As described in this issue of the Biochemical Journal, Nichols et al. have developed an extensive set of molecular tools, including an optimized peptide substrate for determining in vitro kinase activity of LRRK2, a set of kinase inhibitors that can be used to explore LRRK2 substrate specificity and biology, a much-needed murine-specific antibody for immunoprecipation, and efficient gene-silencing approaches. In the present commentary, we discuss some of the components of this new LRRK2 biochemical toolbox and how they can be used to better understand this enigmatic kinase.
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Manzoni, Claudia. "LRRK2 and autophagy: a common pathway for disease." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1147–51. http://dx.doi.org/10.1042/bst20120126.
Повний текст джерелаАнотація:
LRRK2 (leucine-rich repeat kinase 2) is an enzyme implicated in human disease, containing kinase and GTPase functions within the same multidomain open reading frame. Dominant mutations in the LRRK2 gene are the most common cause of familial PD (Parkinson's disease). Additionally, in genome-wide association studies, the LRRK2 locus has been linked to risk of PD, Crohn's disease and leprosy, and LRRK2 has also been linked with cancer. Despite its association with human disease, very little is known about its pathophysiology. Recent reports suggest a functional association between LRRK2 and autophagy. Implications of this set of data for our understanding of LRRK2′s role in physiology and disease are discussed in the present paper.
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Wallings, Rebecca L., and Malú G. Tansey. "LRRK2 regulation of immune-pathways and inflammatory disease." Biochemical Society Transactions 47, no. 6 (November 26, 2019): 1581–95. http://dx.doi.org/10.1042/bst20180463.
Повний текст джерелаАнотація:
Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene are associated with familial and sporadic cases of Parkinson's disease but are also found in immune-related disorders such as inflammatory bowel disease, tuberculosis and leprosy. LRRK2 is highly expressed in immune cells and has been functionally linked to pathways pertinent to immune cell function, such as cytokine release, autophagy and phagocytosis. Here, we examine the current understanding of the role of LRRK2 kinase activity in pathway regulation in immune cells, drawing upon data from multiple diseases associated with LRRK2 to highlight the pleiotropic effects of LRRK2 in different cell types. We discuss the role of the bona fide LRRK2 substrate, Rab GTPases, in LRRK2 pathway regulation as well as downstream events in the autophagy and inflammatory pathways.
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Iannotta, Lucia, and Elisa Greggio. "LRRK2 signaling in neurodegeneration: two decades of progress." Essays in Biochemistry 65, no. 7 (December 2021): 859–72. http://dx.doi.org/10.1042/ebc20210013.
Повний текст джерелаАнотація:
Abstract Leucine-rich repeat kinase 2 (LRRK2) is a complex GTPase/kinase orchestrating cytoskeletal dynamics and multiple steps of the endolysosomal pathway through interaction with a host of partners and phosphorylation of a subset of Rab GTPases. Mutations in LRRK2 cause late-onset Parkinson's disease (PD) and common variants in the locus containing LRRK2 have been associated with sporadic PD, progressive supranuclear palsy as well as a number of inflammatory diseases. This review encompasses the major discoveries in the field of LRRK2 pathobiology, from the initial gene cloning to the latest progress in LRRK2 inhibition as a promising therapeutic approach to fight neurodegeneration.
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Araki, Miho, Kyohei Ito, Sho Takatori, Genta Ito, and Taisuke Tomita. "BORCS6 is involved in the enlargement of lung lamellar bodies in Lrrk2 knockout mice." Human Molecular Genetics 30, no. 17 (June 2, 2021): 1618–31. http://dx.doi.org/10.1093/hmg/ddab146.
Повний текст джерелаАнотація:
Abstract Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson disease. It has been shown that Lrrk2 knockout (KO) rodents have enlarged lamellar bodies (LBs) in their alveolar epithelial type II cells, although the underlying mechanisms remain unclear. Here we performed proteomic analyses on LBs isolated from Lrrk2 KO mice and found that the LB proteome is substantially different in Lrrk2 KO mice compared with wild-type mice. In Lrrk2 KO LBs, several Rab proteins were increased, and subunit proteins of BLOC-1-related complex (BORC) were decreased. The amount of surfactant protein C was significantly decreased in the bronchoalveolar lavage fluid obtained from Lrrk2 KO mice, suggesting that LB exocytosis is impaired in Lrrk2 KO mice. We also found that the enlargement of LBs is recapitulated in A549 cells upon KO of LRRK2 or by treating cells with LRRK2 inhibitors. Using this model, we show that KO of BORCS6, a BORC subunit gene, but not other BORC genes, causes LB enlargement. Our findings implicate the LRRK2-BORCS6 pathway in the maintenance of LB morphology.
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Marchand, Antoine, Alessia Sarchione, Panagiotis S. Athanasopoulos, Hélène Bauderlique-Le Roy, Liesel Goveas, Romain Magnez, Matthieu Drouyer, et al. "A Phosphosite Mutant Approach on LRRK2 Links Phosphorylation and Dephosphorylation to Protective and Deleterious Markers, Respectively." Cells 11, no. 6 (March 17, 2022): 1018. http://dx.doi.org/10.3390/cells11061018.
Повний текст джерелаАнотація:
The Leucine Rich Repeat Kinase 2 (LRRK2) gene is a major genetic determinant of Parkinson’s disease (PD), encoding a homonymous multi-domain protein with two catalytic activities, GTPase and Kinase, involved in intracellular signaling and trafficking. LRRK2 is phosphorylated at multiple sites, including a cluster of autophosphorylation sites in the GTPase domain and a cluster of heterologous phosphorylation sites at residues 860 to 976. Phosphorylation at these latter sites is found to be modified in brains of PD patients, as well as for some disease mutant forms of LRRK2. The main aim of this study is to investigate the functional consequences of LRRK2 phosphorylation or dephosphorylation at LRRK2’s heterologous phosphorylation sites. To this end, we generated LRRK2 phosphorylation site mutants and studied how these affected LRRK2 catalytic activity, neurite outgrowth and lysosomal physiology in cellular models. We show that phosphorylation of RAB8a and RAB10 substrates are reduced with phosphomimicking forms of LRRK2, while RAB29 induced activation of LRRK2 kinase activity is enhanced for phosphodead forms of LRRK2. Considering the hypothesis that PD pathology is associated to increased LRRK2 kinase activity, our results suggest that for its heterologous phosphorylation sites LRRK2 phosphorylation correlates to healthy phenotypes and LRRK2 dephosphorylation correlates to phenotypes associated to the PD pathological processes.
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Kotlica, Boba, Momčilo Ristanović, and Ivana Novaković. "Analysis of rs34637584 polymorphism in the LRRK2 gene in patients with Parkinson's disease." Medicinski podmladak 73, no. 3 (2022): 33–37. http://dx.doi.org/10.5937/mp73-35222.
Повний текст джерелаАнотація:
Introduction: Parkinson's disease (PD) belongs to neurodegenerative diseases, and since the prevalence is 1% to 2% in people older than 65 years and over 4% in people older than 85 years, it is the second most common disease in this group. The cause of PD is the death of dopaminergic neurons in the CNS, primarily in the basal ganglia and the substantia nigra. The LRRK2/PARK8 gene is located on the short arm of chromosome 12. There are many variants in this gene associated with PD, and the most common of which is mutation c.6055G>A (p.Gly2019Ser), also referred to as rs34637584. Aim: The aim of this study was to determine the frequency of the c.6055G>A (rs34637584) mutation in the LRRK2 gene in a group of patients with PD from Serbia. Material and methods: The study included a group of 127 patients with PD from tertiary healthcare institutions in Serbia, as well as an appropriate control group without neurological diseases. Molecular genetic analysis was performed by real-time PCR, using a commercial TaqMan assay. Results: Mutation c.6055G>A ie. rs34637584 variant was detected in 1 of 127 examinees with PD (0.7%). That patient was without a previous family history of PD. This mutation was not found in the control group. Conclusion: The results obtained align with findings of previous studies for the European, especially the southern European population. If these results would be confirmed in a larger patient sample, testing of LRRK2 mutation c.6055G>A (rs34637584) should become part of the PD test protocol.
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Li, Tianxia, Bo Ning, Lingbo Kong, Bingling Dai, Xiaofei He, Joseph M. Thomas, Akira Sawa, Christopher A. Ross та Wanli W. Smith. "A LRRK2 GTP Binding Inhibitor, 68, Reduces LPS-Induced Signaling Events and TNF-α Release in Human Lymphoblasts". Cells 10, № 2 (23 лютого 2021): 480. http://dx.doi.org/10.3390/cells10020480.
Повний текст джерелаАнотація:
Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson’s disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn’s disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders.
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Toh, Joanne, Ling Ling Chua, Patrick Ho, Edwin Sandanaraj, Carol Tang, Hongyan Wang, and Eng King Tan. "Identification of Targets from LRRK2 Rescue Phenotypes." Cells 10, no. 1 (January 5, 2021): 76. http://dx.doi.org/10.3390/cells10010076.
Повний текст джерелаАнотація:
Parkinson’s disease (PD) is an age-dependent neurodegenerative condition. Leucine-rich repeat kinase 2 (LRRK2) mutations are the most frequent cause of sporadic and autosomal dominant PD. The exact role of LRRK2 protective variants (R1398H, N551K) together with a pathogenic mutant (G2019S) in aging and neurodegeneration is unknown. We generated the following myc-tagged UAS-LRRK2 transgenic Drosophila: LRRK2 (WT), N551K, R1398H, G2019S single allele, and double-mutants (N551K/G2019S or R1398H/G2019S). The protective variants alone were able to suppress the phenotypic effects caused by the pathogenic LRRK2 mutation. Next, we conducted RNA-sequencing using mRNA isolated from dopaminergic neurons of these different groups of transgenic Drosophila. Using pathway enrichment analysis, we identified the top 10 modules (p < 0.05), with “LRRK2 in neurons in Parkinson’s disease” among the candidates. Further dissection of this pathway identified the most significantly modulated gene nodes such as eEF1A2, ACTB, eEF1A, and actin cytoskeleton reorganization. The induction of the pathway was successfully restored by the R1398H protective variant and R1398H-G2019S or N551K-G2019S rescue experiments. The oxidoreductase family of genes was also active in the pathogenic mutant and restored in protective and rescue variants. In summary, we provide in vivo evidence supporting the neuroprotective effects of LRRK2 variants. RNA sequencing of dopaminergic neurons identified upregulation of specific gene pathways in the Drosophila carrying the pathogenic variant, and this was restored in the rescue phenotypes. Using protective gene variants, our study identifies potential new targets and provides proof of principle of a new therapeutic approach that will further our understanding of aging and neurodegeneration in PD.
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Sloan, Maximilian, Javier Alegre-Abarrategui, and Richard Wade-Martins. "Insights into LRRK2 function and dysfunction from transgenic and knockout rodent models." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1080–85. http://dx.doi.org/10.1042/bst20120151.
Повний текст джерелаАнотація:
Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene on chromosome 12 cause autosomal dominant PD (Parkinson's disease), which is indistinguishable from sporadic forms of the disease. Numerous attempts have therefore been made to model PD in rodents via the transgenic expression of LRRK2 and its mutant variants and to elucidate the function of LRRK2 by knocking out rodent Lrrk2. Although these models often only partially recapitulate PD pathology, they have helped to elucidate both the normal and pathological function of LRRK2. In particular, LRRK2 has been suggested to play roles in cytoskeletal dynamics, synaptic machinery, dopamine homoeostasis and autophagic processes. Our understanding of how these pathways are affected, their contribution towards PD development and their interaction with one another is still incomplete, however. The present review summarizes the findings from LRRK2 rodent models and draws potential connections between the apparently disparate cellular processes altered, in order to better understand the underlying mechanisms of LRRK2 dysfunction and illuminate future therapeutic interventions.
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Haugarvoll, Kristoffer, Ryan J. Uitti, Matthew J. Farrer, and Zbigniew K. Wszolek. "LRRK2 Gene and Tremor-Dominant Parkinsonism." Archives of Neurology 63, no. 9 (September 1, 2006): 1346. http://dx.doi.org/10.1001/archneur.63.9.1346-b.
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Ciampelli, Cristina, Grazia Galleri, Silvia Puggioni, Milena Fais, Lucia Iannotta, Manuela Galioto, Marta Becciu, et al. "Inhibition of the Exocyst Complex Attenuates the LRRK2 Pathological Effects." International Journal of Molecular Sciences 24, no. 16 (August 10, 2023): 12656. http://dx.doi.org/10.3390/ijms241612656.
Повний текст джерелаАнотація:
Pathological mutations in leucine-rich repeat kinase 2 (LRRK2) gene are the major genetic cause of Parkinson’s disease (PD). Multiple lines of evidence link LRRK2 to the control of vesicle dynamics through phosphorylation of a subset of RAB proteins. However, the molecular mechanisms underlying these processes are not fully elucidated. We have previously demonstrated that LRRK2 increases the exocyst complex assembly by Sec8 interaction, one of the eight members of the exocyst complex, and that Sec8 over-expression mitigates the LRRK2 pathological effect in PC12 cells. Here, we extend this analysis using LRRK2 drosophila models and show that the LRRK2-dependent exocyst complex assembly increase is downstream of RAB phosphorylation. Moreover, exocyst complex inhibition rescues mutant LRRK2 pathogenic phenotype in cellular and drosophila models. Finally, prolonged exocyst inhibition leads to a significant reduction in the LRRK2 protein level, overall supporting the role of the exocyst complex in the LRRK2 pathway. Taken together, our study suggests that modulation of the exocyst complex may represent a novel therapeutic target for PD.
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Ito, Genta, and Naoko Utsunomiya-Tate. "Overview of the Impact of Pathogenic LRRK2 Mutations in Parkinson’s Disease." Biomolecules 13, no. 5 (May 16, 2023): 845. http://dx.doi.org/10.3390/biom13050845.
Повний текст джерелаАнотація:
Leucine-rich repeat kinase 2 (LRRK2) is a large protein kinase that physiologically phosphorylates and regulates the function of several Rab proteins. LRRK2 is genetically implicated in the pathogenesis of both familial and sporadic Parkinson’s disease (PD), although the underlying mechanism is not well understood. Several pathogenic mutations in the LRRK2 gene have been identified, and in most cases the clinical symptoms that PD patients with LRRK2 mutations develop are indistinguishable from those of typical PD. However, it has been shown that the pathological manifestations in the brains of PD patients with LRRK2 mutations are remarkably variable when compared to sporadic PD, ranging from typical PD pathology with Lewy bodies to nigral degeneration with deposition of other amyloidogenic proteins. The pathogenic mutations in LRRK2 are also known to affect the functions and structure of LRRK2, the differences in which may be partly attributable to the variations observed in patient pathology. In this review, in order to help researchers unfamiliar with the field to understand the mechanism of pathogenesis of LRRK2-associated PD, we summarize the clinical and pathological manifestations caused by pathogenic mutations in LRRK2, their impact on the molecular function and structure of LRRK2, and their historical background.
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Galper, Jasmin, Woojin S. Kim, and Nicolas Dzamko. "LRRK2 and Lipid Pathways: Implications for Parkinson’s Disease." Biomolecules 12, no. 11 (October 30, 2022): 1597. http://dx.doi.org/10.3390/biom12111597.
Повний текст джерелаАнотація:
Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed.
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Kalogeropulou, Alexia F., Jordana B. Freemantle, Pawel Lis, Edmundo G. Vides, Nicole K. Polinski, and Dario R. Alessi. "Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity." Biochemical Journal 477, no. 22 (November 27, 2020): 4397–423. http://dx.doi.org/10.1042/bcj20200458.
Повний текст джерелаАнотація:
Mutations that enhance LRRK2 protein kinase activity cause inherited Parkinson's disease. LRRK2 phosphorylates a group of Rab GTPase proteins, including Rab10 and Rab12, within the effector-binding switch-II motif. Previous work has indicated that the PARK16 locus, which harbors the gene encoding for Rab29, is involved in Parkinson's, and that Rab29 operates in a common pathway with LRRK2. Co-expression of Rab29 and LRRK2 stimulates LRRK2 activity by recruiting LRRK2 to the surface of the trans Golgi network. Here, we report that knock-out of Rab29 does not influence endogenous LRRK2 activity, based on the assessment of Rab10 and Rab12 phosphorylation, in wild-type LRRK2, LRRK2[R1441C] or VPS35[D620N] knock-in mouse tissues and primary cell lines, including brain extracts and embryonic fibroblasts. We find that in brain extracts, Rab12 phosphorylation is more robustly impacted by LRRK2 inhibitors and pathogenic mutations than Rab10 phosphorylation. Transgenic overexpression of Rab29 in a mouse model was also insufficient to stimulate basal LRRK2 activity. We observed that stimulation of Rab10 and Rab12 phosphorylation induced by agents that stress the endolysosomal system (nigericin, monensin, chloroquine and LLOMe) is suppressed by LRRK2 inhibitors but not blocked in Rab29 deficient cells. From the agents tested, nigericin induced the greatest increase in Rab10 and Rab12 phosphorylation (5 to 9-fold). Our findings indicate that basal, pathogenic, as well as nigericin and monensin stimulated LRRK2 pathway activity is not controlled by Rab29. Further work is required to establish how LRRK2 activity is regulated, and whether other Rab proteins can control LRRK2 by targeting it to diverse membranes.
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De Wit, Tina, Veerle Baekelandt, and Evy Lobbestael. "LRRK2 Phosphorylation: Behind the Scenes." Neuroscientist 24, no. 5 (January 31, 2018): 486–500. http://dx.doi.org/10.1177/1073858418756309.
Повний текст джерелаАнотація:
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are known today as the most common genetic cause of Parkinson’s disease (PD). LRRK2 is a large protein that is hypothesized to regulate other proteins as a scaffold in downstream signaling pathways. This is supported by the multiple domain composition of LRRK2 with several protein-protein interaction domains combined with kinase and GTPase activity. LRRK2 is highly phosphorylated at sites that are strictly controlled by upstream regulators, including its own kinase domain. In cultured cells, most pathogenic mutants display increased autophosphorylation at S1292, but decreased phosphorylation at sites controlled by other kinases. We only begin to understand how LRRK2 phosphorylation is regulated and how this impacts its physiological and pathological function. Intriguingly, LRRK2 kinase inhibition, currently one of the most prevailing disease-modifying therapeutic strategies for PD, induces LRRK2 dephosphorylation at sites that are also dephosphorylated in pathogenic variants. In addition, LRRK2 kinase inhibition can induce LRRK2 protein degradation, which might be related to the observed inhibitor-induced adverse effects on the lung in rodents and non-human primates, as it resembles the lung pathology in LRRK2 knock-out animals. In this review, we will provide an overview of how LRRK2 phosphorylation is regulated and how this complex regulation relates to several molecular and cellular features of LRRK2.
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Cookson, Mark R. "Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease." Biochemical Society Transactions 44, no. 6 (December 2, 2016): 1603–10. http://dx.doi.org/10.1042/bst20160228.
Повний текст джерелаАнотація:
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, associated with Parkinson's disease, have been shown to affect intracellular trafficking pathways in a variety of cells and organisms. An emerging theme is that LRRK2 can bind to multiple membranous structures in cells, and several recent studies have suggested that the Rab family of small GTPases might be important in controlling the recruitment of LRRK2 to specific cellular compartments. Once localized to membranes, LRRK2 then influences downstream events, evidenced by changes in the autophagy–lysosome pathway. Here, I will discuss available evidence that supports or challenges this outline, with a specific emphasis on those aspects of LRRK2 function that have been controversial or remain to be fully clarified.
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Rivero-Ríos, Pilar, Maria Romo-Lozano, Belén Fernández, Elena Fdez, and Sabine Hilfiker. "Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations." Cells 9, no. 7 (July 17, 2020): 1719. http://dx.doi.org/10.3390/cells9071719.
Повний текст джерелаАнотація:
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson’s disease, and sequence variations are associated with the sporadic form of the disease. LRRK2 phosphorylates a subset of RAB proteins implicated in secretory and recycling trafficking pathways, including RAB8A and RAB10. Another RAB protein, RAB29, has been reported to recruit LRRK2 to the Golgi, where it stimulates its kinase activity. Our previous studies revealed that G2019S LRRK2 expression or knockdown of RAB8A deregulate epidermal growth factor receptor (EGFR) trafficking, with a concomitant accumulation of the receptor in a RAB4-positive recycling compartment. Here, we show that the G2019S LRRK2-mediated EGFR deficits are mimicked by knockdown of RAB10 and rescued by expression of active RAB10. By contrast, RAB29 knockdown is without effect, but expression of RAB29 also rescues the pathogenic LRRK2-mediated trafficking deficits independently of Golgi integrity. Our data suggest that G2019S LRRK2 deregulates endolysosomal trafficking by impairing the function of RAB8A and RAB10, while RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2.
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Cheng, Xiaojuan, Xilin Wu, Yuying Zhang, Weian Li, Linjuan Feng, Hanlin You, Siyu Yang, Dongping Yang, Xiaochun Chen, and Xiaodong Pan. "LRRK2 Deficiency Aggravates Sleep Deprivation-Induced Cognitive Loss by Perturbing Synaptic Pruning in Mice." Brain Sciences 12, no. 9 (September 6, 2022): 1200. http://dx.doi.org/10.3390/brainsci12091200.
Повний текст джерелаАнотація:
Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are associated with pronounced sleep disorders or cognitive dysfunction in neurodegenerative diseases. However, the effects of LRRK2 deficiency on sleep rhythms and sleep deprivation-related cognitive changes, and the relevant underlying mechanism, remain unrevealed. In this study, Lrrk2-/- and Lrrk2+/+ mice were subjected to normal sleep (S) or sleep deprivation (SD). Sleep recording, behavioral testing, Golgi-cox staining, immunofluorescence, and real-time PCR were employed to evaluate the impacts of LRRK2 deficiency on sleep behaviors and to investigate the underlying mechanisms. The results showed that after SD, LRRK2-deficient mice displayed lengthened NREM and shortened REM, and reported decreased dendritic spines, increased microglial activation, and synaptic endocytosis in the prefrontal cortex. Meanwhile, after SD, LRRK2 deficiency aggravated cognitive impairments, especially in the recall memory cued by fear conditioning test. Our findings evidence that LRRK2 modulates REM/NREM sleep and its deficiency may exacerbate sleep deprivation-related cognitive disorders by perturbing synaptic plasticity and microglial synaptic pruning in mice.
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Rivero-Ríos, Pilar, Patricia Gómez-Suaga, Belén Fernández, Jesús Madero-Pérez, Andrew J. Schwab, Allison D. Ebert, and Sabine Hilfiker. "Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson's disease." Biochemical Society Transactions 43, no. 3 (June 1, 2015): 390–95. http://dx.doi.org/10.1042/bst20140301.
Повний текст джерелаАнотація:
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene comprise the most common cause of familial Parkinson's disease (PD), and variants increase the risk for sporadic PD. LRRK2 displays kinase and GTPase activity, and altered catalytic activity correlates with neurotoxicity, making LRRK2 a promising therapeutic target. Despite the importance of LRRK2 for disease pathogenesis, its normal cellular function, and the mechanism(s) by which pathogenic mutations cause neurodegeneration remain unclear. LRRK2 seems to regulate a variety of intracellular vesicular trafficking events to and from the late endosome in a manner dependent on various Rab proteins. At least some of those events are further regulated by LRRK2 in a manner dependent on two-pore channels (TPCs). TPCs are ionic channels localized to distinct endosomal structures and can cause localized calcium release from those acidic stores, with downstream effects on vesicular trafficking. Here, we review current knowledge about the link between LRRK2, TPC- and Rab-mediated vesicular trafficking to and from the late endosome, highlighting a possible cross-talk between endolysosomal calcium stores and Rab proteins underlying pathomechanism(s) in LRRK2-related PD.
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Esteves, A. Raquel, and Sandra M. Cardoso. "LRRK2 at the Crossroad Between Autophagy and Microtubule Trafficking." Neuroscientist 23, no. 1 (July 8, 2016): 16–26. http://dx.doi.org/10.1177/1073858415616558.
Повний текст джерелаАнотація:
Mutations in leucine-rich repeat kinase 2 ( lrrk2) gene cause inherited Parkinson’s disease (PD), and common variants in lrrk2 are a risk factor for sporadic PD. The neuropathology associated with LRRK2-linked PD is extremely pleomorphic involving inclusions of α-synuclein (SNCA), tau or neither, therefore suggesting that LRRK2 may be central in the pathogenic pathways of PD. This large protein localizes in the cytosol, as well as, in specific membrane domains, including mitochondria and autophagosomes and interacts with a wide range of proteins such as SNCA, tau, α- and β-tubulin. For this reason LRRK2 has been associated with a variety of cellular functions, including autophagy, mitochondrial function/dynamics and microtubule/cytoskeletal dynamics. LRRK2 has been shown to interact with microtubules as well as with mitochondria interfering with their network and dynamics. Moreover, LRRK2 knock-out or mutations affect autophagic efficiency. Here, we review and discuss the literature on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology.
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Bonet-Ponce, Luis, Alexandra Beilina, Chad D. Williamson, Eric Lindberg, Jillian H. Kluss, Sara Saez-Atienzar, Natalie Landeck, et al. "LRRK2 mediates tubulation and vesicle sorting from lysosomes." Science Advances 6, no. 46 (November 2020): eabb2454. http://dx.doi.org/10.1126/sciadv.abb2454.
Повний текст джерелаАнотація:
Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson’s disease (PD). However, the biological functions of LRRK2 remain incompletely understood. Here, we report that LRRK2 is recruited to lysosomes after exposure of cells to the lysosome membrane–rupturing agent LLOME. Using an unbiased proteomic screen, we identified the motor adaptor protein JIP4 as an LRRK2 partner at the lysosomal membrane. LRRK2 can recruit JIP4 to lysosomes in a kinase-dependent manner via the phosphorylation of RAB35 and RAB10. Using super-resolution live-cell imaging microscopy and FIB-SEM, we demonstrate that JIP4 promotes the formation of LAMP1-negative tubules that release membranous content from lysosomes. Thus, we describe a new process orchestrated by LRRK2, which we name LYTL (LYsosomal Tubulation/sorting driven by LRRK2), by which lysosomal tubulation is used to release vesicles from lysosomes. Given the central role of the lysosome in PD, LYTL is likely to be disease relevant.
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Wang, Shijie, and Andrew B. West. "Caught in the act: LRRK2 in exosomes." Biochemical Society Transactions 47, no. 2 (March 5, 2019): 663–70. http://dx.doi.org/10.1042/bst20180467.
Повний текст джерелаАнотація:
Abstract Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a frequent genetic cause of late-onset Parkinson's disease (PD) and a target for therapeutic approaches. LRRK2 protein can influence vesicle trafficking events in the cytosol, with action both in endosomal and lysosomal pathways in different types of cells. A subset of late endosomes harbor intraluminal vesicles that can be secreted into the extracellular milieu. These extracellular vesicles, called exosomes, package LRRK2 protein for transport outside the cell into easily accessed biofluids. Both the cytoplasmic complement of LRRK2 as well as the exosome-associated fraction of protein appears regulated in part by interactions with 14-3-3 proteins. LRRK2 inside exosomes have disease-linked post-translational modifications and are relatively stable compared with unprotected proteins in the extracellular space or disrupted cytosolic compartments. Herein, we review the biology of exosome-associated LRRK2 and the potential for utility in diagnosis, prognosis, and theragnosis in PD and other LRRK2-linked diseases.
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Chittoor-Vinod, Vinita G., R. Jeremy Nichols, and Birgitt Schüle. "Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism." International Journal of Molecular Sciences 22, no. 3 (January 21, 2021): 1045. http://dx.doi.org/10.3390/ijms22031045.
Повний текст джерелаАнотація:
Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson’s disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2, p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer’s pathology, hailing LRRK2 parkinsonism as the “Rosetta stone” of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors—either increasing toxicity or providing resilience—will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and LRRK2-related neurodegeneration.
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Kalogeropulou, Alexia F., Jing Zhao, Marc F. Bolliger, Anna Memou, Shreya Narasimha, Tyler P. Molitor, William H. Wilson, Hardy J. Rideout, and R. Jeremy Nichols. "P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity." Biochemical Journal 475, no. 7 (April 9, 2018): 1271–93. http://dx.doi.org/10.1042/bcj20170699.
Повний текст джерелаАнотація:
Autosomal-dominant, missense mutations in the leucine-rich repeat protein kinase 2 (LRRK2) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations (N1437H, R1441C/G/H, Y1699C, G2019S), implicating hyperphosphorylation of a substrate in the pathogenesis of the disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in the disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and a substrate of LRRK2. Using mass spectrometry and phospho-specific antibodies, we found that LRRK2 phosphorylates p62 on Thr138 in vitro and in cells. We found that the pathogenic LRRK2 PD-associated mutations (N1437H, R1441C/G/H, Y1699C, G2019S) increase phosphorylation of p62 similar to previously reported substrate Rab proteins. Notably, we found that the pathogenic I2020T mutation and the risk factor mutation G2385R displayed decreased phosphorylation of p62. p62 phosphorylation by LRRK2 is blocked by treatment with selective LRRK2 inhibitors in cells. We also found that the amino-terminus of LRRK2 is crucial for optimal phosphorylation of Rab7L1 and p62 in cells. LRRK2 phosphorylation of Thr138 is dependent on a p62 functional ubiquitin-binding domain at its carboxy-terminus. Co-expression of p62 with LRRK2 G2019S increases the neurotoxicity of this mutation in a manner dependent on Thr138. p62 is an additional novel substrate of LRRK2 that regulates its toxic biology, reveals novel signaling nodes and can be used as a pharmacodynamic marker for LRRK2 kinase activity.
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Т.С., Усенко,, Башарова, К.С., Безрукова, А.И., Николаев, М.А., Милюхина, И.В., Байдакова, Г.В., Захарова, Е.Ю., and Пчелина, С.Н. "Selective inhibition of LRRK2 activity as an approach to the treatment of Parkinson's disease." Nauchno-prakticheskii zhurnal «Medicinskaia genetika, no. 12 (December 26, 2022): 26–29. http://dx.doi.org/10.25557/2073-7998.2022.12.26-29.
Повний текст джерелаАнотація:
На сегодняшний день не существует нейропротекторных препаратов для лечения распространённого нейродегенеративного заболевания болезни Паркинсона (БП). Наиболее перспективной для разработки тагретной терапии считается форма БП, ассоциированная с мутациями в гене GBA (GBA-БП), как самая распространенная форма БП с известной этиологией. Мутации в гене GBA, кодирующем фермент глюкоцереброзидазу (GCase), приводят к снижению активности данного фермента. Ранее было показано, что ингибирование киназной активности LRRK2 ингибитором MLi-2 приводит к увеличению активности GCase. В данном исследовании мы впервые показали влияние ингибитора киназной активности LRRK2 MLi-2 не только на активность GCase, но и на активность других лизосомных ферментов в первичной культуре макрофагов периферической крови пациентов не только с LRRK2-ассоциированной БП (LRRK2-БП), но и с GBA-БП. To date, there are no neuroprotective drugs for the common neurodegenerative disease, Parkinson’s disease (PD). PD associated with mutations in the GBA gene (GBA-PD) is the most common form of PD with a known etiology. GBA-PD is considered the most promising for the development of therapy for PD. Mutations in the GBA gene encoding the enzyme glucocerebrosidase (GCase) lead to a decrease in the activity of this enzyme. Previously, it was shown that inhibition of LRRK2 kinase activity by MLi-2 inhibitor leads to an increase in GCase activity. In this study, we showed for the first time the effect of the LRRK2 kinase activity inhibitor MLi-2 not only on the activity of GCase, but also on the activity of other lysosomal enzymes in the primary culture of peripheral blood macrophages of patients with LRRK2-associated PD (LRRK2-PD) and GBA-PD.
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Greggio, Elisa. "Role of LRRK2 kinase activity in the pathogenesis of Parkinson's disease." Biochemical Society Transactions 40, no. 5 (September 19, 2012): 1058–62. http://dx.doi.org/10.1042/bst20120054.
Повний текст джерелаАнотація:
Interest in studying the biology of LRRK2 (leucine-rich repeat kinase 2) started in 2004 when missense mutations in the LRRK2 gene were linked to an inherited form of Parkinson's disease with clinical and pathological presentation resembling the sporadic syndrome. LRRK2 is a complex molecule containing domains implicated in protein interactions, as well as kinase and GTPase activities. The observation that the common G2019S mutation increases kinase activity in vitro suggests that altered phosphorylation of LRRK2 targets may have pathological outcomes. Given that protein kinases are ideal targets for drug therapies, much effort has been directed at understanding the role of LRRK2 kinase activity on disease onset. However, no clear physiological substrates have been identified to date, indicating that much research is still needed to fully understand the signalling pathways orchestrated by LRRK2 and deregulated under pathological conditions.
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Vlachakis, Dimitrios, Nikolaos Labrou, Costas Iliopoulos, John Hardy, Patrick Lewis, Hardy Rideout, and Daniah Trabzuni. "Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2." International Journal of Molecular Sciences 19, no. 9 (September 16, 2018): 2784. http://dx.doi.org/10.3390/ijms19092784.
Повний текст джерелаАнотація:
Leucine-rich repeat kinase 2 (LRRK2) is a large protein of unclear function. Rare mutations in the LRRK2 gene cause familial Parkinson’s disease (PD) and inflammatory bowel disease. Genome-wide association studies (GWAS) have revealed significant association of the abovementioned diseases at the LRRK2 locus. Cell and systems biology research has led to potential roles that LRRK2 may have in PD pathogenesis, especially the kinase domain (KIN). Previous human expression studies showed evidence of mRNA expression and splicing patterns that may contribute to our understanding of the function of LRRK2. In this work, we investigate and identified significant regional differences in LRRK2 expression at the mRNA level, including a number of splicing events in the Ras of complex protein (Roc) and C-terminal of Roc domain (COR) of LRRK2, in the substantia nigra (SN) and occipital cortex (OCTX). Our findings indicate that the predominant form of LRRK2 mRNA is full length, with shorter isoforms present at a lower copy number. Our molecular modelling study suggests that splicing events in the ROC/COR domains will have major consequences on the enzymatic function and dimer formation of LRRK2. The implications of these are highly relevant to the broader effort to understand the biology and physiological functions of LRRK2, and to better characterize the role(s) of LRRK2 in the underlying mechanism leading to PD.
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Takagawa, Tetsuya, Atsushi Kitani, Ivan Fuss, Beth Levine, Steven R. Brant, Inga Peter, Masaki Tajima, Shiro Nakamura, and Warren Strober. "An increase in LRRK2 suppresses autophagy and enhances Dectin-1–induced immunity in a mouse model of colitis." Science Translational Medicine 10, no. 444 (June 6, 2018): eaan8162. http://dx.doi.org/10.1126/scitranslmed.aan8162.
Повний текст джерелаАнотація:
The LRRK2/MUC19 gene region constitutes a high-risk genetic locus for the occurrence of both inflammatory bowel diseases (IBDs) and Parkinson’s disease. We show that dendritic cells (DCs) from patients with Crohn’s disease (CD) and lymphoblastoid cell lines derived from patients without CD but bearing a high-risk allele (rs11564258) at this locus as heterozygotes exhibited increased LRRK2 expression in vitro. To investigate the immunological consequences of this increased LRRK2 expression, we conducted studies in transgenic mice overexpressing Lrrk2 and showed that these mice exhibited more severe colitis induced by dextran sodium sulfate (DSS) than did littermate control animals. This increase in colitis severity was associated with lamina propria DCs that showed increased Dectin-1–induced NF-κB activation and proinflammatory cytokine secretion. Colitis severity was driven by LRRK2 activation of NF-κB pathway components including the TAK1 complex and TRAF6. Next, we found that membrane-associated LRRK2 (in association with TAB2) caused inactivation of Beclin-1 and inhibition of autophagy. HCT116 colon epithelial cells lacking Beclin-1 exhibited increased LRRK2 expression compared to wild-type cells, suggesting that inhibition of autophagy potentially could augment LRRK2 proinflammatory signaling. We then showed that LRRK2 inhibitors decreased Dectin-1–induced TNF-α production by mouse DCs and ameliorated DSS-induced colitis, both in control and Lrrk2 transgenic animals. Finally, we demonstrated that LRRK2 inhibitors blocked TNF-α production by cultured DCs from patients with CD. Our findings suggest that normalization of LRRK2 activation could be a therapeutic approach for treating IBD, regardless of whether a LRRK2 risk allele is involved.