Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

Daher, João Paulo Lima; Abdelmotilib, Hisham; Hu, Xianzhen; Volpicelli‐Daley, Laura A.; Moehle, Mark S.; Fraser, Kyle; Needle, Elie; Chen, Yi; Steyn, Stefanus J.; Galatsis, Paul; Hirst, Warren D.; West, Andrew B.

doi:10.1074/jbc.m115.660001

Cited by 177 publications

(198 citation statements)

References 42 publications

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“…The excellent tolerability of MLi-2 after subchronic dosing is particularly encouraging as a recent publication by Fuji et al, (2015) raised significant concerns over the tolerability of repeated administration of LRRK2 kinase inhibitors. That LRRK2 inhibition by MLi-2 is well-tolerated by rodents agrees well with a recent report demonstrating good tolerability with another LRRK2 kinase inhibitor (PFE-06447475) after chronic administration (Daher et al, 2015). Both MLi-2 and PFE-06447475 have higher potency and selectivity for LRRK2 (Henderson et al, 2015) compared with GNE-0877 and GNE-7915 (Fuji et al, 2015), thus it seems probable that adverse effects observed with GNE-0877 and GNE-7915 are not LRRK2-mediated and are most probably the result of an as yet to be determined off target activity.…”

Section: Discussionsupporting

confidence: 75%

“…To the best of our knowledge these are the first data showing that pharmacological inhibition of LRRK2 kinase activity in rodents can recapitulate the lung phenotype observed in LRRK2 KO animals. Previous reports have failed to observe the induction of the lung phenotype or the reduction in LRRK2 protein levels in mice and rats treated with LRRK2 for up to 28 days (Henderson et al, 2015;Daher et al, 2015;Fuji et al, 2015). However, the induction of lung phenotypes in rodents may require sustained LRRK2 inhibition and/or, longer treatment durations than previously achieved.…”

Section: Discussionmentioning

confidence: 65%

See 1 more Smart Citation

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

Fell

Mirescu

Basu

et al. 2015

J Pharmacol Exp Ther

240

294

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of familial and sporadic Parkinson's disease (PD). That the most prevalent mutation, G2019S, leads to increased kinase activity has led to a concerted effort to identify LRRK2 kinase inhibitors as a potential disease-modifying therapy for PD. An internal medicinal chemistry effort identified several potent and highly selective compounds with favorable drug-like properties. Here, we characterize the pharmacological properties of cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi-2), a structurally novel, highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC 50 5 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC 50 5 1.4 nM), and a radioligand competition binding assay (IC 50 5 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels. Acute oral and subchronic dosing in MLi-2 mice resulted in dosedependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 was well tolerated over a 15-week period at brain and plasma exposures .100Â the in vivo plasma IC 50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, were observed in MLi-2-treated MitoPark mice. These data demonstrate the suitability of MLi-2 as a compound to explore LRRK2 biology in cellular and animal models.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 65%

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

Fell

Mirescu

Basu

et al. 2015

J Pharmacol Exp Ther

240

294

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“…Although the G2019S-LRRK2 BAC rat does not show dopaminergic neurodegeneration or changes in TH expression in the striatum due to the transgene expression (Daher et al, 2015), we next sought to determine whether the fibril or monomer injection caused a loss of neurons in either G2019S-LRRK2 or nonTg rats that might confound our analysis 1 month after injection. We performed unbiased stereology of TH-positive neurons in the SNpc and found a normal cell count in both nonTg and G2019S-LRRK2-expressing rats.…”

Section: Enhanced Inclusions In Th-positive Neurons In the Snpc Of G2mentioning

confidence: 99%

“…Mice coexpressing LRRK2 with the pathogenic G2019S mutation and ␣-synuclein with the pathogenic A53T mutation show increased neurodegeneration and increased ␣-synuclein aggregate formation (Lin et al, 2009;Daher et al, 2012). In addition, death of substantia nigra dopaminergic neurons induced by viral overexpression of ␣-synuclein is exacerbated in rats expressing G2019S-LRRK2 (Daher et al, 2015). Although mice overexpressing mutant ␣-synuclein either through transgenes or viral transduction provide a valuable tool for understanding the impact of abnormal ␣-synuclein in vivo, ␣-synuclein aggregation is often coincident with cell death and/or mortality; thus, the progression of inclusion formation over time is difficult to analyze with conventional staining techniques (Giasson et al, 2002;Lee et al, 2002), although newer in vivo imaging approaches may be able to provide some insight (Osterberg et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

G2019S-LRRK2 Expression Augments -Synuclein Sequestration into Inclusions in Neurons

Volpicelli‐Daley

Abdelmotilib

et al. 2016

Journal of Neuroscience

161

143

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Pathologic inclusions define ␣-synucleinopathies that include Parkinson's disease (PD).The most common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity. However, the interaction between ␣-synuclein, LRRK2, and the formation of ␣-synuclein inclusions remains unclear. Here, we show that G2019S-LRRK2 expression, in both cultured neurons and dopaminergic neurons in the rat substantia nigra pars compact, increases the recruitment of endogenous ␣-synuclein into inclusions in response to ␣-synuclein fibril exposure. This results from the expression of mutant G2019S-LRRK2, as overexpression of WT-LRRK2 not only does not increase formation of inclusions but reduces their abundance. In addition, treatment of primary mouse neurons with LRRK2 kinase inhibitors, PF-06447475 and MLi-2, blocks G2019S-LRRK2 effects, suggesting that the G2019S-LRRK2 potentiation of inclusion formation depends on its kinase activity. Overexpression of G2019S-LRRK2 slightly increases, whereas WT-LRRK2 decreases, total levels of ␣-synuclein. Knockdown of total ␣-synuclein with potent antisense oligonucleotides substantially reduces inclusion formation in G2019S-LRRK2-expressing neurons, suggesting that LRRK2 influences ␣-synuclein inclusion formation by altering ␣-synuclein levels. These findings support the hypothesis that G2019S-LRRK2 may increase the progression of pathological ␣-synuclein inclusions after the initial formation of ␣-synuclein pathology by increasing a pool of ␣-synuclein that is more susceptible to forming inclusions.

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“…G2019S-LRRK2 transgenic rats exhibit exacerbated inflammation and DA neurodegeneration caused by overexpression of α-synuclein. Administration of PF-06447475 ameliorates these effects and has neuroprotective effects in wild-type rats [69]. In G2019S-LRRK2 knock-in mice, Ser129-phosphorylated α-synuclein overload at DA terminals occurs in an age-dependent manner, along with the progressive dysfunction of dopamine transporters [70].…”

Section: Lrrk2 As a Therapeutic Targetmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Chen¹,

Chen²,

Pu³

2018

Eur Neurol

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Background: Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Summary: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment.

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Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

Cited by 177 publications

References 42 publications

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

G2019S-LRRK2 Expression Augments -Synuclein Sequestration into Inclusions in Neurons

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

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