Role and mechanism of action of leucine-rich repeat kinase 1 in bone

Xing, Weirong; Goodluck, Helen; Zeng, Canjun; Mohan, Subburaman

doi:10.1038/boneres.2017.3

Cited by 23 publications

(23 citation statements)

References 118 publications

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“…Importantly, all residues affected by pathogenic mutations in humans are conserved in rodent LRRK2 ( Langston et al, 2016 ). Rodents also possess a LRRK1 homolog, which shares ankyrin repeats (ANK), leucine-rich repeats (LRR), and Roc, COR, and kinase domains with LRRK2, but may also contain a WD40 domain that is still contested in the literature ( Biskup et al, 2007 ; Civiero et al, 2012 ; Sejwal et al, 2017 ; Xing et al, 2017 ). The dopaminergic neuroanatomical pathways of rodents and humans are also highly similar, leading to the development of an array of sensitive behavioral tests in rodents that may correlate to dopamine loss in human PD ( Meredith and Kang, 2006 ; Redgrave et al, 2010 ).…”

Section: Rodent Lrrk2 Modelsmentioning

confidence: 99%

Progress in LRRK2-Associated Parkinson’s Disease Animal Models

et al. 2020

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). Several genetic manipulations of the LRRK2 gene have been developed in animal models such as rodents, Drosophila, Caenorhabditis elegans, and zebrafish. These models can help us further understand the biological function and derive potential pathological mechanisms for LRRK2. Here we discuss common phenotypic themes found in LRRK2-associated PD animal models, highlight several issues that should be addressed in future models, and discuss emerging areas to guide their future development.

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Section: Rodent Lrrk2 Modelsmentioning

confidence: 99%

Progress in LRRK2-Associated Parkinson’s Disease Animal Models

et al. 2020

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“…Collectively, the three allometry QTL intervals were significantly enriched for genes implicated in bone development (FDR q = 0.025). Each of the intervals included at least one such gene: Nab1 (chromosome 1) [90], Foxp1 (chromosome 6) [91,92], and Lrrk1 and Chsy1 (chromosome 7) [93][94][95]. The chromosome 1 interval also includes Myostatin (Mstn, Gdf8), a negative regulator of muscle growth.…”

Section: Biological Process Enrichmentmentioning

confidence: 99%

Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

et al. 2020

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The biology of how faces are built and come to differ from one another is complex. Discovering normal variants that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in mouse), each characterized by 22 three-dimensional landmarks, 56,885 autosomal and Xchromosome markers, and sex and age classifiers. We identified 37 facial shape QTL across 20 shape principal components (PCs) using a mixed effects regression that accounts for kinship among observations. The QTL include some previously identified intervals as well as new regions that expand the list of potential targets for future experimental study. Three QTL characterized shape associations with size (allometry). Median support interval size was 3.5 Mb. Narrowing additional analysis to QTL for the five largest magnitude shape PCs, we found significant overrepresentation of genes with known roles in growth, skeletal and facial development, and sensory organ development. For most intervals, one or more of these genes lies within 0.25 Mb of the QTL's peak. QTL effect sizes were small, with none explaining more than 0.5% of facial shape variation. Thus, our results are consistent with a model of facial diversity that is influenced by key genes in skeletal and facial development and, simultaneously, is highly polygenic.

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“…Homology-based protein modeling of the hLRRK1 KD indicated that the LRRK1 KD contains an extra loop in the activation site compared with the hLRRK2 KD [18], and it has a narrower active pocket for ligand binding (Figure 1A). A total of approximately 5,000 KINACore and 11,000 KINASet compounds were screened.…”

Section: Resultsmentioning

confidence: 99%

A small molecular inhibitor of LRRK1 identified by homology modeling and virtual screening suppresses osteoclast function, but not osteoclast differentiation, in vitro

Zeng

Goodluck

et al. 2019

Aging

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We used TGFβ activation kinase 1 as a template to build a 3D structure of the human LRRK1 kinase domain (hLRRK1 KD) and performed small molecule docking. One of the chemicals (IN04) that docked into the pocket was chosen for evaluation of biological effects on osteoclasts (OCs) in vitro . INO4 at 16 nM completely blocked ATP binding to hLRRK1 KD in an in vitro pulldown assay. In differentiation and pit assays, while the number of OCs on bone slices were comparable for OCs treated with IN04 and DMSO, IN04 treatment of OCs significantly impaired their ability to resorb bone. The area of pits on bone slices was reduced by 43% at 5 μM and 83% at 10 μM as compared to DMSO. Individual pits appeared smaller and shallower. F-actin staining revealed that DMSO-treated OCs displayed clear actin rings, and F-actin forms a peripheral sealing zone. By contrast, IN04-treated OCs showed disarranged F-actin in the cytoplasm, and F-actin failed to form a sealing zone on bone slices. IN04 treatment had no effects on OC-derived coupling factor production nor on osteoblast nodule formation. Our data indicate IN04 is a potent inhibitor of LRRK1, suppressing OC function with no effect on OC formation.

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Role and mechanism of action of leucine-rich repeat kinase 1 in bone

Cited by 23 publications

References 118 publications

Progress in LRRK2-Associated Parkinson’s Disease Animal Models

Progress in LRRK2-Associated Parkinson’s Disease Animal Models

Facial shape and allometry quantitative trait locus intervals in the Diversity Outbred mouse are enriched for known skeletal and facial development genes

A small molecular inhibitor of LRRK1 identified by homology modeling and virtual screening suppresses osteoclast function, but not osteoclast differentiation, in vitro

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