68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment

Thomas, J. M.; Li, Tianxia; Yang, Wei; Xue, Fengtian; Fishman, Paul S.; Smith, Wanli W.

doi:10.3389/fnagi.2016.00337

Cited by 25 publications

(27 citation statements)

References 59 publications

(101 reference statements)

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“…Recent studies have described the identification of several LRRK2 GTP-binding inhibitors able to attenuate LRRK2 toxicity, and able to rescue vesicular transport deficits associated with impaired neurite outgrowth ( 39–41 ). Both compound 68 and compound 70 significantly reduced LRRK2 GTP binding in vitro ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Various independent studies have reported that LRRK2 interacts with MTs, even though a preferential association with dynamic versus stable MTs has remained unclear ( 31 , 33–35 ). Whilst the presence of LRRK2 in growth cones has been taken to indicate that it may preferentially interact with dynamic MTs ( 39 ), such localization may be contributed to by additional factors. Furthermore, the previously reported alternating nature between the presence of pathogenic LRRK2 and acetylated α-tubulin staining has been taken as evidence that it interacts with dynamic MTs ( 35 ), but our data suggest this to be an unlikely interpretation for several reasons.…”

Section: Discussionmentioning

confidence: 99%

“…Such colocalization has also been observed with overexpressed LRRK2, and is profoundly enhanced with certain pathogenic LRRK2 mutants ( 34 , 35 ) as well as by several LRRK2 kinase inhibitors ( 36–38 ). Finally, pathogenic LRRK2 has been reported to impair MT-mediated axonal transport in a manner correlated with enhanced MT association ( 35 , 39 ). Thus, an increased interaction of LRRK2 with MTs seems to have detrimental effects on MT-mediated vesicular transport events.…”

Section: Introductionmentioning

confidence: 99%

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GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2

Ramírez

Ordóñez

Fdez

et al. 2017

Human Molecular Genetics

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Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise the most common cause of familial Parkinson's disease (PD), and sequence variants modify risk for sporadic PD. Previous studies indicate that LRRK2 interacts with microtubules (MTs) and alters MT-mediated vesicular transport processes. However, the molecular determinants within LRRK2 required for such interactions have remained unknown. Here, we report that most pathogenic LRRK2 mutants cause relocalization of LRRK2 to filamentous structures which colocalize with a subset of MTs, and an identical relocalization is seen upon pharmacological LRRK2 kinase inhibition. The pronounced colocalization with MTs does not correlate with alterations in LRRK2 kinase activity, but rather with increased GTP binding. Synthetic mutations which impair GTP binding, as well as LRRK2 GTP-binding inhibitors profoundly interfere with the abnormal localization of both pathogenic mutant as well as kinase-inhibited LRRK2. Conversely, addition of a non-hydrolyzable GTP analog to permeabilized cells enhances the association of pathogenic or kinase-inhibited LRRK2 with MTs. Our data elucidate the mechanism underlying the increased MT association of select pathogenic LRRK2 mutants or of pharmacologically kinase-inhibited LRRK2, with implications for downstream MT-mediated transport events.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2

Ramírez

Ordóñez

Fdez

et al. 2017

Human Molecular Genetics

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“…Therefore, we conclude that pathogenic LRRK2 antagonizes not only the TRIM32-induced miRNA activity but also neuronal differentiation. Finally, since reduced neurite complexity is a well-known characteristic of in vitro cell culture models for PD [ 27 ], we also analyzed this feature. In the here used assay, expression of TRIM32 had no effect on neurite number, branching, or length.…”

Section: Resultsmentioning

confidence: 99%

Parkinson’s Disease-Associated Mutant LRRK2-Mediated Inhibition of miRNA Activity is Antagonized by TRIM32

et al. 2017

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Accumulating evidences suggest that PD might have a strong neurodevelopmental component. Among the genetic cases, mutations in the leucine-rich repeat kinase 2 (LRRK2) are well known to be disease causing. Although the molecular mechanism of the pathogenic LRRK2 function is not fully clear, inhibition of microRNA (miRNA) activity has been suggested to be among the pathogenic LRRK2 targets. Here, we demonstrate that the miRNA activity inhibition function of pathogenic LRRK2 is directly antagonized by the neuronal cell fate determinant TRIM32. These findings suggest that TRIM32 might be a modifier for PD and could be a novel therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-017-0570-y) contains supplementary material, which is available to authorized users.

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“…Putative pharmacological inhibitors of LRRK2 GTPbinding have also been reported (i.e. FX2149) although their selectivity profiles and mode of action are poorly defined (53,54).…”

Section: G2019s Mutation In Vivomentioning

confidence: 99%

Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

Nguyen

Tsika

Kelly

et al. 2019

Preprint

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and represent the most common known cause of PD. LRRK2 can function as both a protein kinase and GTPase and PDlinked mutations are known to influence both of these enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage and toxicity in cellular models, the mechanisms underlying these pathogenic effects remain uncertain.Rodent models based upon familial LRRK2 mutations often lack the hallmark features of PD and robust neurodegenerative phenotypes in general. Here, we develop a robust pre-clinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of full-length human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or in-diet dosing with the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the selective and robust destabilization of human LRRK2 protein in the rat brain relative to endogenous LRRK2. Our study further demonstrates that dopaminergic neurodegeneration induced by G2019S LRRK2 critically requires normal GTPase activity. The introduction of hypothesis-testing mutations that increase GTP hydrolysis or impair GTP binding activity provide neuroprotection against G2019S LRRK2 via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

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68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment

Cited by 25 publications

References 59 publications

GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2

GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2

Parkinson’s Disease-Associated Mutant LRRK2-Mediated Inhibition of miRNA Activity is Antagonized by TRIM32

Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

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