Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents

West, Andrew B.; Cowell, Rita M.; Daher, João Paulo Lima; Moehle, Mark S.; Hinkle, Kelly M.; Melrose, Heather L.; Standaert, David G.; Volpicelli‐Daley, Laura A.

doi:10.1002/cne.23583

Cited by 120 publications

(94 citation statements)

References 46 publications

(72 reference statements)

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“…LRRK2 protein is well documented to be found at highest levels in the striatum in mammals (Galter et al, 2006; Melrose et al, 2006; Taymans et al, 2006; Higashi et al, 2007a; Higashi et al, 2007b; Melrose et al, 2007; Westerlund et al, 2008a; Westerlund et al, 2008b; Mandemakers et al, 2012; Davies et al, 2013a; Giesert et al, 2013; West et al, 2014). Therefore we reasoned that the G2019S mutation might impact on the functional integrity of the nigro-striatal dopaminergic pathway.…”

Section: Resultsmentioning

confidence: 99%

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Yue

Hinkle

Davies

et al. 2015

Neurobiology of Disease

221

214

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Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson’s disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug- evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

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Section: Resultsmentioning

confidence: 99%

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Yue

Hinkle

Davies

et al. 2015

Neurobiology of Disease

221

214

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“…Primary antibodies were incubated for 24-48 h followed by secondary antibodies overnight. The following primary antibodies were used: human-specific α-synuclein syn208 and nitrosylated α-synuclein Syn514 (both courtesy of the Virginia Lee laboratory and previously characterized) (19,22,23), TH (Sigma and Santa Cruz), CD68 (AdSerotec), EGFP (Santa Cruz), GFAP (Sigma), LRRK2 (NeuroMAB N241), and Iba1 (Wako). For immunohistochemistry, the ABC (Avidin-Biotin Complex reagent, Vector Labs) kit was used with ImmPACT-DAB (3, 3′-diaminobenzidine) substrate (Vector Labs).…”

Section: Methodsmentioning

confidence: 99%

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Daher

Volpicelli‐Daley

Blackburn

et al. 2014

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

Self Cite

200

208

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Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disorders. These discrepancies may be caused by uncertainty in the pathobiological mechanisms of LRRK2 action. Previously, we found that LRRK2 knockdown inhibited proinflammatory responses from cultured microglia cells. Here, we report LRRK2 knockout rats as resistant to dopaminergic neurodegeneration elicited by intracranial administration of LPS. Such resistance to dopaminergic neurodegeneration correlated with reduced proinflammatory myeloid cells recruited in the brain. Additionally, adeno-associated virus-mediated transduction of human α-synuclein also resulted in dopaminergic neurodegeneration in wild-type rats. In contrast, LRRK2 knockout animals had no significant loss of neurons and had reduced numbers of activated myeloid cells in the substantia nigra. Although LRRK2 expression in the wild-type rat midbrain remained undetected under nonpathological conditions, LRRK2 became highly expressed in inducible nitric oxide synthase (iNOS)-positive myeloid cells in the substantia nigra in response to α-synuclein overexpression or LPS exposures. Our data suggest that knocking down LRRK2 may protect from overt cell loss by inhibiting the recruitment of chronically activated proinflammatory myeloid cells. These results may provide value in the translation of LRRK2-targeting therapeutics to conditions where neuroinflammation may underlie aspects of neuronal dysfunction and degeneration.M issense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can be found in many families that transmit classical late-onset Parkinson disease (PD) from one generation to the next. Notably, these mutations are prevalent in the Ashkenazi Jewish and North African Arab Berber populations in more than 20% of PD cases (1, 2). Genome-wide association studies further provide evidence that links LRRK2 to PD susceptibility, with several risk alleles being identified in LRRK2 (3, 4). Association studies have also linked LRRK2 to Crohn disease and Hansen disease (5, 6). Although LRRK2 is widely considered an exciting target for therapeutic approaches in PD, the pathobiological role of LRRK2 as a critical modifier of disease susceptibility is not well understood. Additional insights into LRRK2-linked molecular pathways relevant to PD and neurodegeneration may enable more predictive preclinical studies.PD is pathologically characterized by both α-synuclein inclusions called Lewy bodies and Lewy neurites and the profound loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The absence of LRRK2 has been shown to impair α-synuclein inclusion formation, neuron loss, and microglia activation in mice overexpressing mutant α-synuclein (7). However, other studies that have crossed LRRK2 knockout mice with different α-synuclein transgenic mice did not observe robust protection fr...

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“…Whereas, in mice, LRRK2 has a relatively widespread distribution, in rats the distribution is much more restricted (West et al, 2014). Of particular note, high levels of LRRK2 have been detected in the dopaminergic cell body region of the substantia nigra pars compacta in mice, but not in rats.…”

Section: Basic Functional Differences Between Mouse and Rat Brainsmentioning

confidence: 99%

Rodent models in neuroscience research: is it a rat race?

Ellenbroek

Youn

2016

Disease Models &Amp; Mechanisms

488

379

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Rodents (especially Mus musculus and Rattus norvegicus) have been the most widely used models in biomedical research for many years. A notable shift has taken place over the last two decades, with mice taking a more and more prominent role in biomedical science compared to rats. This shift was primarily instigated by the availability of a much larger genetic toolbox for mice, particularly embryonic-stem-cell-based targeting technology for gene disruption. With the recent emergence of tools for altering the rat genome, notably genome-editing technologies, the technological gap between the two organisms is closing, and it is becoming more important to consider the physiological, anatomical, biochemical and pharmacological differences between rats and mice when choosing the right model system for a specific biological question. The aim of this short review and accompanying poster is to highlight some of the most important differences, and to discuss their impact on studies of human diseases, with a special focus on neuropsychiatric disorders.

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Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents

Cited by 120 publications

References 46 publications

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Rodent models in neuroscience research: is it a rat race?

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