Enhanced Striatal Dopamine Transmission and Motor Performance with LRRK2 Overexpression in Mice Is Eliminated by Familial Parkinson's Disease Mutation G2019S

Li, Xianting; Patel, Jyoti; Wang, Jing; Avshalumov, Marat V.; Nicholson, Charles; Buxbaum, Joseph D.; Elder, Gregory A.; Rice, Margaret E.; Yue, Zhenyu

doi:10.1523/jneurosci.5604-09.2010

Cited by 326 publications

(382 citation statements)

References 51 publications

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“…Consistent with this partial loss-of-function pathogenic mechanism, expression of various mutant forms of LRRK2 in mice, even at more than 10-fold of overproduction, has so far failed to reproduce PD-like neuropathological changes, such as cell death and α-synuclein aggregation (35)(36)(37)(38). Interestingly, a recent report showed that LRRK2 inactivation alleviated rather than exacerbated α-synuclein aggregation and neurodegeneration under overexpression conditions (>16-fold) in α-synuclein transgenic mice (37).…”

Section: Discussionmentioning

confidence: 97%

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Tong

Yamaguchi

Giaime

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

468

499

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2 −/− mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2 −/− kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time.Parkinson's disease | knockout | autophagy | ubiquitin-proteasome system | aging P arkinson's disease (PD) is the most common movement disorder. The neuropathological hallmarks of PD are progressive degeneration of dopaminergic (DA) neurons and the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies, of which α-synuclein is a major constituent (1). Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial PD (2, 3), highlighting the importance of LRRK2 in PD pathogenesis; however, the normal physiological role of LRRK2 is unknown. LRRK2 is a large protein containing a Ras-like small GTPase domain and a MAPKKK-like kinase domain, and has a functional homolog LRRK1, which shares similar domain structures (4). Crystal structural and biochemical studies showed that the GTPase domain forms a dimer; the pathogenic mutations destabilize the dimer and reduce GTPase activity (5-7). A recent in vitro study suggested that LRRK2 and LRRK1 can interact with each other and form a heterodimer (8). Although no physiological substrate of the LRRK2 kinase activity has been reported, studies in cultured cells have suggested that some pathogenic mutations in LRRK2 cause increases in LRRK2 kinase activity (9, 10).Protein aggregation is thought to play a major role in neurodegeneration and PD pathogenesis (11). The strongest evidence came from studies of α-synuclein. Gene multiplication and missense mutations in α-synuclein have been identified in early-onset familial PD with dominant inheritance (12). α-Synuclein is a major constituent of Lewy bodies (1). Overexpression of either WT or mutant α-synuclein in transgenic mice causes age-related neurodegeneration (13-15). Although patients carryi...

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Section: Discussionmentioning

confidence: 97%

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Tong

Yamaguchi

Giaime

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

468

499

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“…31,32 As shown in Figure 2, robust concentration-dependent knockdown of phospho-LRRK2 (pLRRK2) levels in the brain was observed after ip dosing at 10 or 15 mg/kg. Inhibition modeling indicates the in vivo unbound brain IC 50 of 18 to be 12 nM.…”

Section: P Arkinson's Disease (Pd) Is a Neurodegenerative Disordermentioning

confidence: 95%

Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor

Chan¹,

Estrada²,

Chen³

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilinoaminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs. KEYWORDS: LRRK2, kinase inhibitor, Parkinson's disease, CYP1A2 inhibition P arkinson's disease (PD) is a neurodegenerative disorder that affects approximately 1% of the world's population over the age of 65. 1 Identification of a disease-modifying or neuroprotective therapeutic for PD patients remains a significant challenge. Recently, genetic research has revealed a connection between a missense mutation (G2019S) in the leucine-rich repeat kinase 2 (LRRK2) gene and a number of familial and idiopathic PD cases. 2−9 Significantly, multiple reports have shown that this mutation enhances the kinase activity of LRRK2. 10−17 The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has therefore been proposed as a potential treatment for PD. 18−23 We recently reported the first disclosure of a series of highly potent, selective, and brain-penetrable anilino-pyrimidine LRRK2 inhibitors as exemplified by compound 1. 22,23 Examination of the liabilities of 1 and structurally similar analogues revealed (a) moderate to poor aqueous solubility (thermodynamic solubility of 1 at pH 7.4 < 0.9 μg/mL), (b) potential for ortho-quinoneimine reactive metabolite formation, and (c) a morpholinocarboxamide motif as a major site of metabolism as indicated by metabolite identification studies (MetID). In an effort to improve upon 1 and mitigate potential safety risks, we initiated a campaign to identify a suitable bioisosteric replacement for the aniline functionality. This approach resulted in the discovery of a novel series of highly selective aminopyrazole LRRK2 inhibitors.Docking experiments using a JAK-2-derived homology model of LRRK2 suggested that compound 1 binds in the ATP binding site of LRRK2 as shown in Figure 1. 22,23 In designing anilino-carboxamide replacements, we chose to retain the hinge binding diaminopyrimidine core as well as the C-5 trifluoromethyl group that interacts favorably with the methionine gatekeeper through van der Waal contacts. Additionally, our lead optimization efforts toward 1 established the importance of occupying the vector adjacent to the hingebinding anilino N-H motif (methoxy group in...

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“…Two transgenic mouse models overexpressing human G2019S LRRK2 exhibit modest age-dependent DA neuron loss associated with accumulation of autophagosomes and mitochondrial alterations [124,125], but other G2019S LRRK2 transgenic mouse models had diminished dopamine transmission and motor deficits without detectable neuron loss [53,54]. The only I2020T LRRK2 transgenic mouse model reported to date exhibits no obvious loss of DA neurons [126].…”

Section: Direct Toxic Effects Of Lrrk2 Expression In Neuronsmentioning

confidence: 99%

“…The physiological function of LRRK2 is unknown, but LRRK2 is involved in autophagy [49,50], vesicle sorting and trafficking [51,52], dopamine homeostasis [53,54], dopamine receptor activation, synaptogenesis [55], and cytoskeleton dynamics (Fig. 2) [56,57].…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Enhanced Striatal Dopamine Transmission and Motor Performance with LRRK2 Overexpression in Mice Is Eliminated by Familial Parkinson's Disease Mutation G2019S

Cited by 326 publications

References 51 publications

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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