LRRK2 Inhibition Attenuates Microglial Inflammatory Responses

Moehle, Mark S.; Webber, Philip J.; Tse, Tonia E.; Sukar, Nour N.; Standaert, David G.; DeSilva, Tara M.; Cowell, Rita M.; West, Andrew B.

doi:10.1523/jneurosci.5601-11.2012

Cited by 389 publications

(433 citation statements)

References 27 publications

(31 reference statements)

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“…Besides neuronal LRRK2 expression, high levels of LRRK2 have been recently detected in activated myeloid lineage cells that include macrophages and microglia (10,11). In cultured rat microglia cells, we found that LRRK2 expression is induced upon activation.…”

mentioning

confidence: 58%

“…In vitro evidence suggests that LRRK2 knockdown attenuates proinflammatory responses induced by LPS exposure (10). We first evaluated several endotoxin dosages of ultrapurified LPS (Invivogen, Inc.) in rodents and found that 50 kE.U.…”

Section: Resultsmentioning

confidence: 99%

“…LRRK2 expression has been detected in activated myeloid cells in the periphery and brain (10,11). We used CD68, a glycoprotein expressed in cells of the myeloid lineage, as a marker for activated microglia, macrophages, and monocytes.…”

Section: Resultsmentioning

confidence: 99%

“…In cultured rat microglia cells, we found that LRRK2 expression is induced upon activation. RNA-interference knockdown of LRRK2 reduces immune responses induced by the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) (10). Both LPS exposure and overexpression of human α-synuclein via viral vectors produce selective dopaminergic neuron death in rodents (12,13), but LRRK2 function has not been previously evaluated in either model system.…”

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confidence: 99%

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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.

195

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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mentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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.

195

208

View full text Add to dashboard Cite

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“…It was also demonstrated that in a macrophagic cell line (RAW264.7) and a microglial cell line (BV2), stimulation of toll‐like receptors 2 and 4 (TLR2, TLR4) was able to increase phosphorylation of LRRK2 and induce its recruitment to membranes 67, 109. Finally, toll‐like receptor 4 stimulation was able to increase LRRK2 expression and phosphorylation in primary rat microglia 158. LRRK2 was described as a negative regulator of nuclear factor of activated T cells (NFAT), a protein involved in transcriptional regulation in T cells, macrophages, dendritic cells and neutrophils 162; reinforcing the hypothesis that LRRK2 may have a precise role in the immune system because of the peculiar interaction partners through which it can exert tissue‐specific functions.…”

Section: Lrrk2 and The Immune Systemmentioning

confidence: 94%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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

West

Cowell

Daher

et al. 2014

J of Comparative Neurology

116

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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.

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LRRK2 Inhibition Attenuates Microglial Inflammatory Responses

Cited by 389 publications

References 27 publications

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

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

Cellular processes associated with LRRK2 function and dysfunction

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

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