Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers

Caesar, Mareike; Felk, Sandra; Aasly, Jan; Gillardon, Frank

doi:10.1016/j.neuroscience.2014.09.070

Cited by 25 publications

(27 citation statements)

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“…; Caesar et al . ). We therefore pursued the hypothesis of PAK6 as a potential interactor with, and mediator of the biological effects of, LRRK2.…”

Section: Resultsmentioning

confidence: 97%

“…PAK6 belongs to group II p21-activated kinases (PAKs), a family of proteins involved in cell remodeling pathways via regulation of actin cytoskeleton dynamics (Szczepanowska 2009), processes where also LRRK2 has been implicated (Meixner et al 2011;Habig et al 2013;Caesar et al 2015). We therefore pursued the hypothesis of PAK6 as a potential interactor with, and mediator of the biological effects of, LRRK2.…”

Section: Lrrk2 Interacts With Pak6mentioning

confidence: 99%

“…Special interest has been directed at understanding the cellular functions of LRRK2, given that mutations in this gene are a common cause of Parkinson's disease (PD) (Paisan-Ruiz et al 2004Zimprich et al 2004). LRRK2 has been linked with several pathways relevant for neuronal physiology, including autophagy (Plowey et al 2008;Gomez-Suaga et al 2012;Manzoni et al 2013), vesicle trafficking (Piccoli et al 2011;MacLeod et al 2013;Cirnaru et al 2014), neurite outgrowth (MacLeod et al 2006;Dachsel et al 2010;Winner et al 2011), cytoskeletal dynamics (Kett et al 2011;Caesar et al 2013Caesar et al , 2015Habig et al 2013;Law et al 2013), and inflammation (reviewed in Russo et al 2014). Although some of these functions may appear unrelated, they all rely on the presence of a functional cytoskeleton.…”

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confidence: 99%

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Leucine‐rich repeat kinase 2 interacts with p21‐activated kinase 6 to control neurite complexity in mammalian brain

Civiero

Cirnaru

Beilina

et al. 2015

Journal of Neurochemistry

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Leucine-rich repeat kinase 2 (LRRK2) is a causative gene for Parkinson's disease but the physiological function and the mechanism(s) by which the cellular activity of LRRK2 is regulated are poorly understood. Here, we identified p21-activated kinase 6 (PAK6) as a novel interactor of the GTPase/ROC domain of LRRK2. PAKs are serine-threonine kinases that serve as targets for the small GTP binding proteins Cdc42 and Rac1 and have been implicated in different morphogenetic processes through remodeling of the actin cytoskeleton such as synapse formation and neuritogenesis. Using an in vivo neuromorphology assay, we show that PAK6 is a positive regulator of neurite outgrowth and that LRRK2 is required for this function. Analyses of post-mortem brain tissue from idiopathic and LRRK2 G2019S carriers reveal an increase in PAK6 activation state, whereas knock-out LRRK2 mice display reduced PAK6 activation and phosphorylation of PAK6 substrates. Taken together, these results support a critical role of LRRK2 GTPase domain in cytoskeletal dynamics in vivo through the novel interactor PAK6, and provide a valuable platform to unravel the mechanism underlying LRRK2-mediated pathophysiology.

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“…; Caesar et al . ). We therefore pursued the hypothesis of PAK6 as a potential interactor with, and mediator of the biological effects of, LRRK2.…”

Section: Resultsmentioning

confidence: 97%

Section: Lrrk2 Interacts With Pak6mentioning

confidence: 99%

mentioning

confidence: 99%

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Leucine‐rich repeat kinase 2 interacts with p21‐activated kinase 6 to control neurite complexity in mammalian brain

Civiero

Cirnaru

Beilina

et al. 2015

Journal of Neurochemistry

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“…Fibroblasts have previously been characterized in cases of familial PD, and we and others have determined robust mitochondrial phenotypes from lines harboring LRRK2 [9–13], PINK1 [10, 15], and Parkin [16–20] mutations, both at baseline and under conditions of pharmacological stress. Therefore, in this series of experiments, we have investigated whether sporadic (non-familial) PD patient-derived fibroblast lines also show mitochondrial phenotypes and compare them against lines derived from LRRK2 mutation (G2019S and R1441C) carrying PD patients.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we and others have characterized mitochondrial phenotypes in fibroblast cell lines harboring LRRK2 [9–14], PTEN-induced putative kinase 1 (PINK1) [8, 10, 15], and Parkin [16–20] mutations, both at baseline and under conditions of pharmacological stress. Specifically, mutant LRRK2 carrying fibroblast lines have been instrumental to investigate mitochondrial phenotypes and hence, have recently been used for exploratory drug screens [21].…”

Section: Introductionmentioning

confidence: 99%

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

et al. 2015

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It has been uncertain whether specific disease-relevant biomarker phenotypes can be found using sporadic Parkinson’s disease (PD) patient-derived samples, as it has been proposed that there may be a plethora of underlying causes and pathological mechanisms. Fibroblasts derived from familial PD patients harboring leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), and Parkin mutations show clear disease-relevant mitochondrial phenotypes, which are exacerbated under conditions of pharmacological stress. We utilized fibroblasts derived from non-familial sporadic PD patients (without LRRK2 mutations) or LRRK2 mutation carriers to directly compare the cellular phenotypes during and after mitochondrial stress. We then determined the effects of pharmacological LRRK2 kinase inhibition using LRRK2-in-1. We found that there were two distinct populations of sporadic PD patient-derived fibroblast lines. One group of sporadic PD lines was highly susceptible to valinomycin-induced mitochondrial depolarization, emulating the mutant LRRK2 phenotype. These lines showed elevated mitochondrial superoxide/ nitric oxide levels, displayed increased mitochondrial and lysosome co-localization, and an increased rate of mitochondrial collapse, which corresponded with changes in mitochondrial fission and fusion proteins. The application of LRRK2-in-1 reversed decreased levels of mitochondrial and lysosome co-localization and partially restored mitochondrial network associated proteins and the mitochondrial membrane potential in the fibroblasts. This study identifies novel mitochondrial biomarkers in sporadic PD patient-derived fibroblast lines, which could be used as preclinical tools in which to test novel and known neuroprotective compounds.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9435-4) contains supplementary material, which is available to authorized users.

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Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Lai¹,

Alipanahi²,

Fontanillas³

et al. 2021

Annals of Neurology

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ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age‐at‐onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age‐at‐onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non‐cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age‐at‐onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age‐at‐onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E‐08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co‐immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E‐07; age‐at‐onset top variant: p value = 9.3E‐07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age‐at‐onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82–94

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Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers

Cited by 25 publications

References 61 publications

Leucine‐rich repeat kinase 2 interacts with p21‐activated kinase 6 to control neurite complexity in mammalian brain

Leucine‐rich repeat kinase 2 interacts with p21‐activated kinase 6 to control neurite complexity in mammalian brain

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

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