High LRRK2 Levels Fail to Induce or Exacerbate Neuronal Alpha-Synucleinopathy in Mouse Brain

Department of Neuroscience, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
PLoS ONE (Impact Factor: 3.23). 05/2012; 7(5):e36581. DOI: 10.1371/journal.pone.0036581
Source: PubMed


The G2019S mutation in the multidomain protein leucine-rich repeat kinase 2 (LRRK2) is one of the most frequently identified genetic causes of Parkinson's disease (PD). Clinically, LRRK2(G2019S) carriers with PD and idiopathic PD patients have a very similar disease with brainstem and cortical Lewy pathology (α-synucleinopathy) as histopathological hallmarks. Some patients have Tau pathology. Enhanced kinase function of the LRRK2(G2019S) mutant protein is a prime suspect mechanism for carriers to develop PD but observations in LRRK2 knock-out, G2019S knock-in and kinase-dead mutant mice suggest that LRRK2 steady-state abundance of the protein also plays a determining role. One critical question concerning the molecular pathogenesis in LRRK2(G2019S) PD patients is whether α-synuclein (aSN) has a contributory role. To this end we generated mice with high expression of either wildtype or G2019S mutant LRRK2 in brainstem and cortical neurons. High levels of these LRRK2 variants left endogenous aSN and Tau levels unaltered and did not exacerbate or otherwise modify α-synucleinopathy in mice that co-expressed high levels of LRRK2 and aSN in brain neurons. On the contrary, in some lines high LRRK2 levels improved motor skills in the presence and absence of aSN-transgene-induced disease. Therefore, in many neurons high LRRK2 levels are well tolerated and not sufficient to drive or exacerbate neuronal α-synucleinopathy.

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Available from: Derya R Shimshek, Oct 05, 2015
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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.
    The Journal of Comparative Neurology 08/2014; 522(11). DOI:10.1002/cne.23583 · 3.23 Impact Factor
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    • "However, the role of LRRK2 in synucleinopathy has been challenged by other studies. These studies failed to show changes in α-synuclein and glial pathology, neurodegeneration, behavioral deficits, and timing of premature death in LRRK2 G2019S/α-synuclein A53T double transgenic mice, compared to the A53T single transgenic mice, casting a doubt in the role of LRRK2 mutations in α-synuclein-driven pathogenesis [7, 82]. "
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    ABSTRACT: Parkinson's disease (PD) and related Lewy body diseases are characterized by deposition of α-synuclein aggregates in both the central nervous system and peripheral nervous system. Synucleinopathy lesions spread to larger brain areas as the disease progresses, and prion-like cell-to-cell transmission of aggregated α-synuclein is thought to be the underlying mechanism for this pathological spreading. LRRK2 is another protein linked to the pathogenesis of PD, and its presence in Lewy bodies has attracted much attention as to whether LRRK2 and α-synuclein interplay during the pathogenesis of PD. However, the relationship between these two crucial proteins still remains unclear. In this review article, we will discuss the current state of knowledge in terms of how these proteins cause the disease and provide the hypothetical mechanisms by which LRRK2 might modify the generation and progression of synucleinopathy.
    12/2013; 22(4):249-257. DOI:10.5607/en.2013.22.4.249
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    • "According to the literature, other LRRK2 mouse models have also failed to show specific PD motor deficits. Indeed, mouse lines overexpressing the wild type form or the G2019S mutation of the LRRK2 gene displayed hyperactivity and increased motor function [24], [27], while other lines overexpressing the same G2019S mutation or knock-in for the R1441C mutation did not exhibit particular motor disturbances [24], [25], [31], apart from increased thigmotaxis (preference for the area close to the walls) [23]. Similarly, knock-out mice for the LRRK2 gene displayed only increased thigmotaxic behavior in the open field and increased abilities in the rotarod [30]. "
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    ABSTRACT: Non-motor symptoms are increasingly recognized as important features of Parkinson's disease (PD). LRRK2 mutations are common causes of familial and sporadic PD. Non-motor features have not been yet comprehensively evaluated in LRRK2 transgenic mouse models. Using a transgenic mouse model overexpressing the R1441G mutation of the human LRRK2 gene, we have investigated the longitudinal correlation between motor and non-motor symptoms and determined if specific non-motor phenotypes precede motor symptoms. We investigated the onset of motor and non-motor phenotypes on the LRRK2(R1441G) BAC transgenic mice and their littermate controls from 4 to 21 month-old using a battery of behavioral tests. The transgenic mutant mice displayed mild hypokinesia in the open field from 16 months old, with gastrointestinal dysfunctions beginning at 6 months old. Non-motor features such as depression and anxiety-like behaviors, sensorial functions (pain sensitivity and olfaction), and learning and memory abilities in the passive avoidance test were similar in the transgenic animals compared to littermate controls. LRRK2(R1441G) BAC transgenic mice displayed gastrointestinal dysfunction at an early stage but did not have abnormalities in fine behaviors, olfaction, pain sensitivity, mood disorders and learning and memory compared to non-transgenic littermate controls. The observations on olfaction and gastrointestinal dysfunction in this model validate findings in human carriers. These mice did recapitulate mild Parkinsonian motor features at late stages but compensatory mechanisms modulating the progression of PD in these models should be further evaluated.
    PLoS ONE 07/2013; 8(7):e70249. DOI:10.1371/journal.pone.0070249 · 3.23 Impact Factor
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