Li, Y. et al. Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat. Neurosci. 12, 826-828

Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, New York, USA.
Nature Neuroscience (Impact Factor: 16.1). 08/2009; 12(7):826-8. DOI: 10.1038/nn.2349
Source: PubMed


Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. We created a LRRK2 transgenic mouse model that recapitulates cardinal features of the disease: an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection. These mice provide a valid model of Parkinson's disease and are a resource for the investigation of pathogenesis and therapeutics.

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    • "Several previous studies have reported tau-related neuronal pathology in the brains of PD patients with LRRK2 mutations and also in LRRK2-transgenic animal models [69] [70] [71] [72] [73]. In particular, these reports indicated that (i) patients with G2019S mutation of LRRK2 have neurofibrillary tangles composed of phosphorylated tau as an atypical form of tau pathology [71], (ii) phosphorylation of tau is increased in R1441G-and G2019S-LRRK2 transgenic mice [70] [72], whereas tau phosphorylation is decreased in LRRK2- knockout mice [74], and (iii) tau-positive lesions are evident in patients with LRRK2-I2020T mutation [68]. Thus, LRRK2 may play an important role in tau phosphorylation-related neuronal pathology. "
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    ABSTRACT: There is now a considerable body of experimental evidence that Parkinson’s disease arises through physiological interaction of causative molecules, leading to tau pathology. In this review, we discuss the physiological role of α-synuclein and LRRK2 in the abnormal phosphorylation of tau. In addition, as recent reports have indicated that heat shock proteins- (HSPs-) inducing drugs can help to ameliorate neurodegenerative diseases associated with tau pathology, we also discuss therapeutic strategies for PD focusing on inhibition of α-synuclein- and LRRK2-associated tau phosphorylation by HSPs.
    Full-text · Article · May 2015 · Parkinson's Disease
    • "R1441C or Y1699C) outside of the kinase domain to LRRK2-mediated neurodegeneration in this rat adenoviral model will form the focus of our future studies. Similar to some cases of LRRK2-associated PD (Zimprich et al., 2004a, 2004b; Wszolek et al., 2004; Rajput et al., 2006), rodent models of LRRK2 exhibit the modest accumulation of hyperphosphorylated tau or alterations in tau metabolism yet in the absence of frank neurodegeneration (Li et al., 2009, in press; Melrose et al., 2010). Our original study of this adenoviral rat model revealed transient tau hyperphosphorylation localized to nigral dopaminergic neurites induced by expression of WT or G2019S LRRK2, although only G2019S LRRK2 induced dopaminergic neurodegeneration (Dusonchet et al., 2011). "
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    ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 contains functional GTPase and kinase domains. The most common G2019S mutation enhances the kinase activity of LRRK2 in vitro whereas G2019S LRRK2 expression in cultured neurons induces toxicity in a kinase-dependent manner. These observations suggest a potential role for kinase activity in LRRK2-associated PD. We have recently developed a novel rodent model of PD with progressive neurodegeneration induced by the adenoviral-mediated expression of G2019S LRRK2. In the present study, we further characterize this LRRK2 model and determine the contribution of kinase activity to LRRK2-mediated neurodegeneration. Recombinant human adenoviral vectors were employed to deliver human wild-type, G2019S or kinase-inactive G2019S/D1994N LRRK2 to the rat striatum. LRRK2-dependent pathology was assessed in the striatum, a region where LRRK2 protein is normally enriched in the mammalian brain. Human LRRK2 variants are robustly expressed throughout the rat striatum. Expression of G2019S LRRK2 selectively induces the accumulation of neuronal ubiquitin-positive inclusions accompanied by neurite degeneration and the altered distribution of axonal phosphorylated neurofilaments. Importantly, the introduction of a kinase-inactive mutation (G2019S/D1994N) completely ameliorates the pathological effects of G2019S LRRK2 in the striatum supporting a kinase activity-dependent mechanism for this PD-associated mutation. Collectively, our study further elucidates the pathological effects of the G2019S mutation in the mammalian brain and supports the development of kinase inhibitors as a potential therapeutic approach for treating LRRK2-associated PD. This adenoviral rodent model provides an important tool for elucidating the molecular basis of LRRK2-mediated neurodegeneration. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Feb 2015 · Neurobiology of Disease
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    • "Recent emerging evidence suggests interactions between LRRK2 and a-synuclein aggregation (Lin et al., 2009; Orenstein et al., 2013), but this remains controversial (Daher et al., 2012; Herzig et al., 2012). Thus, the cortico–striatal circuit may in part be selectively vulnerable in PD because of the concentration of proteins known to underlie aspects of late-onset PD. "
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    ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are found in a significant proportion of late-onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared to mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2-G2019S protein from mouse BAC constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2-G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and non-human primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate-specific promoter sequence that does not exist in lower mammalian species. These non-coding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2014 · The Journal of Comparative Neurology
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