Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene are associated with familial and sporadic cases of Parkinson's disease but are also found in immune-related disorders such as inflammatory bowel disease, tuberculosis and leprosy. LRRK2 is highly expressed in immune cells and has been functionally linked to pathways pertinent to immune cell function, such as cytokine release, autophagy and phagocytosis. Here, we examine the current understanding of the role of LRRK2 kinase activity in pathway regulation in immune cells, drawing upon data from multiple diseases associated with LRRK2 to highlight the pleiotropic effects of LRRK2 in different cell types. We discuss the role of the bona fide LRRK2 substrate, Rab GTPases, in LRRK2 pathway regulation as well as downstream events in the autophagy and inflammatory pathways.

Introduction

The leucine-rich-repeat kinase 2 (LRRK2) gene encodes for a large, multidomain protein encompassing two enzymatic functions at its core. The catalytic core consists of the GTPase domain of the protein, and the serine/threonine kinase domain, which are surrounded by protein–protein interaction domains. The N-terminal harbours the armadillo, the ankyrin and the leucine-rich-repeat (LRR) domains. At the C-terminal, there is the WD40 domain, which has been demonstrated to be crucial for protein folding [1]. Given the multiple, highly diverse enzymatic and protein-interacting domains, it is likely that LRRK2 may have different binding partners in different cell types and be instrumental in many different cellular pathways.

Mutations in the LRRK2 gene are the most frequent cause of familial Parkinson's disease (PD) [2], with seven pathogenic mutations, which cluster around the catalytic domains of the protein, identified. Clinically, mutant LRRK2-PD patients are often considered indistinguishable from sporadic patients. Therefore, deciphering the role of LRRK2 in PD pathogenesis may reveal common pathological mechanisms underlying idiopathic PD and is consequently of great research importance.

LRRK2 is highly expressed in immune cells and this expression is tightly regulated by immune stimulation. As well, LRRK2 has been biochemically linked to the pathways regulating inflammation as well as autophagy and phagocytosis. There is now mounting evidence that both systemic and central nervous system (CNS) inflammation play a role in PD pathophysiology [3]. Furthermore, polymorphisms in the LRRK2 gene have now been linked to inflammatory diseases such as inflammatory bowel disease (IBD), tuberculosis (TB) and increased susceptibility to leprosy, highlighting a critical role of LRRK2 in inflammation.

This review will outline what is currently understood about LRRK2 function in the regulation of pathways in immune cells. The role of LRRK2 kinase activity in disease will be discussed, as well as recently identified, bona fide LRRK2 protein interactors and the role of LRRK2 in inflammatory signalling pathways and autophagy.

LRRK2 expression in immune cells

The activation of immune cell subsets is critical for a proper and effective immune response to pathogens. For example, activation of T cells leads to the development of cell-mediated immune mechanisms and increased antibody responses which are produced by activated B cells [4]. Human monocytes have been subdivided into different populations based on the surface expression of CD14 and CD16. CD14+ classical monocytes have been observed to be phagocytic with decreased inflammatory attributes, whilst CD16+ non-classical monocytes have been reported to display inflammatory characteristics and display properties for antigen presentation [5]. Activation of immune cells is a healthy response serving to protect and repair the body, however, chronic activation and therefore chronic inflammation is deleterious and damaging.

LRRK2 is a largely ubiquitously expressed protein, and is most abundant in the brain, kidney and lungs. However, increased expression in immune cells, specifically in response to pro-inflammatory signals, has been observed in many immune cell types, strongly implicating LRRK2 as a regulator of the immune response.

Increases in LRRK2 mRNA and protein expression have been observed in response to interferon-γ (IFN-γ) treatment in human B cells, T cells, macrophages [6–9] and non-classical monocytes [9]. Similar increases in LRRK2 protein expression have been observed in response to the toll-like receptor 4 (TLR4) ligand, lipopolysaccharide (LPS) in bone-marrow-derived macrophages (BMDMs) [10] and primary murine-microglia [11] and the cytokine IL-1β [12] in human umbilical vein endothelial cells (HUVECs). Microglia have also been shown to up-regulate LRRK2 protein expression following cranial injection with LPS, as well as increased kinase activity [11].

It has been reported that PD-associated LRRK2 mutations exacerbate LRRK2 expression levels in response to inflammatory stimuli, suggesting a role of LRRK2 in immune cells in PD [13]. This is supported by the observation that the loss of Lrrk2 decreases pro-inflammatory myeloid cells in the brains of rats and decreases neurodegenerative responses to both LPS and α-synuclein [14]. LRRK2 is also up-regulated in unstimulated cells in sporadic-PD neutrophils [15], B cells, T Cells, and CD16+/CD14 non-classical monocytes [7]. Furthermore, inhibition of LRRK2 with multiple kinase inhibitors has been shown to decrease CD14, CD16 and MHC-II expression in human immune cells, suggesting that LRRK2 is playing a significant role in the activation of cells in response to inflammatory stimulation in a kinase-dependent manner [8].

LRRK2 kinase activity in disease

The increased kinase activity of LRRK2 mutants has been linked to the pathological function of LRRK2 in disease. However, when considering different diseases, cell types, and mutations, the role of LRRK2 kinase activity may not be quite as simple as originally thought (Table 1).

Inflammation and LRRK2 in PD

Genome-wide conjunctional analysis has previously identified 17 novel loci that overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2 and MAPT for rheumatoid arthritis and IBD [30]. Furthermore, peripheral pro-inflammatory cytokine levels are higher in a percentage of asymptomatic subjects carrying the G2019S-LRRK2 mutation [16], which consistently increases LRRK2 kinase activity [31-35], suggesting an early role of inflammation in a disease that may be driven by increased kinase levels. Interestingly, systemic LPS administration triggers significant increases in peripheral cytokines in mice expressing R1441G-LRRK2 that exacerbate neuroinflammation in the brain, increases LRRK2 expression in neurons and causes neurodegeneration [17]. The R1441G/C/H mutations, which reside in the GTPase domain, fail to consistently increase LRRK2 kinase activity, with both increases [35–38] and no changes [33,34,39] reported. The role of LRRK2 kinase activity in inflammation observed in these R1441G-LRRK2 mice is therefore unclear.

The effect of LRRK2 kinase inhibitors, LRRK2 knockdown or kinase-dead mutants has resulted in conflicting results in different immune cell types (Table 1). For example, data from HUVECs expressing the G2019S-LRRK2 mutation demonstrate an increase in levels of VCAM-1, which is essential for immune cell trafficking, in response to IL-1β [12]. This phenotype was not recapitulated with the expression of the kinase-dead mutant, K1347A, indicating a kinase-dependent mechanism for LRRK2 in immune responses. This is further supported with evidence from knockout models suggesting a dampened immune response with the loss of LRRK2. For example, loss of Lrrk2 in microglia increases α-synuclein uptake and clearance relative to microglia from wild-type (WT) mice [18]. Furthermore, LRRK2 knockdown or kinase inhibition in primary microglia have been shown to decrease the production of the pro-inflammatory cytokines TNF and IL-1β [11,19]. However, many reports observe no differences in cytokine release with Lrrk2-knockout in BMDMs [10,20]. Interestingly, knockout of Lrrk2 decreases phagocytosis in peripheral myeloid cells, whilst G2019S-LRRK2 expression increases phagocytosis in these cells [21]. Collectively, these data suggest LRRK2 may play distinct roles in immune cells in a cell-type dependent manner. Interestingly, an opposing role of LRRK2 in peripheral and CNS innate immunity has recently been suggested [3], and future research would benefit from directly comparing immune cells from the periphery and CNS.

LRRK2 in leprosy and the lesson of pleiotropy

Leprosy is a chronic dermato-neurological infectious disease caused by Mycobacterium leprae (M. Laprae). It has been demonstrated that LRRK2 variants are significantly associated with leprosy [40]. However, results evaluating the association of LRRK2 variants with leprosy susceptibility have been inconsistent [41–43]. One complication of the disease is excessive inflammation termed as type-1 reactions (T1R) which can lead to pathological immune responses directed against peripheral nerve cells [44]. Eighteen single nucleotide polymorphisms (SNPs) in LRRK2 have been shown to preferentially associate with T1R [45], which may underlie the previously reported inconsistencies. Specifically, one variant identified, M2367T, lies in the WD40 domain of LRRK2 and has previously been shown to increase LRRK2 protein turnover and therefore decrease enzymatic activity [46]. This subsequently increases pro-inflammatory cytokine transcription via NFAT translocation to the nucleus [22], suggesting that LRRK2 pathophysiology in leprosy may be due to a loss or decrease in function.

Intriguingly, antagonistic pleiotropic effects of LRRK2 in leprosy T1R and PD have recently been described. The R1628P-LRRK2 gain-of-kinase function mutation has been shown to be protective for T1R but has been reported as a risk-variant for PD [23]. It was hypothesized that a reduction in apoptosis caused by the R1628P mutation underlies this effect, with apoptotic cells releasing multiple anti-inflammatory mediators [47] whilst also increasing inflammation if not cleared efficiently [48]. This would suggest that the lower yield of apoptotic debris in leprosy patients may protect against T1R whilst the reduction in anti-inflammatory molecules resulting from abrogated apoptosis is disease-promoting in the brain. This data, therefore, implies potential opposing effects of LRRK2 kinase activity on inflammation in the peripheral and CNS.

LRRK2 in tuberculosis and other bacterial infections

LRRK2 has been implicated in several bacterial infections. Interestingly, there are contrasting reports between the effects of kinase inhibition on different bacterial infections, with LRRK2 kinase inhibition enhancing the restriction of some bacteria or increasing susceptibility to infection for others.

TB is an infectious disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb). Numerous SNPs in LRRK2 are associated with susceptibility to mycobacterial infection [40,45]. A statistical meta-analysis of nine published datasets has recently demonstrated that LRRK2 is a differentially expressed gene (DEG) in association with TB [49]. More specifically, LRRK2 also interacts with seven of the other DEGs identified in this study, including two components in the NRON complex through which LRRK2 inhibits the immune response transcription factor NFAT1 [22].

It has recently been demonstrated that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase (PI3K) complex and Rubicon, with kinase inhibition and LRRK2 deficiency enhancing Mtb control and decreasing Mtb burdens [24]. In contrast with the improved control of Mtb replication, loss of LRRK2 has been reported to impair control of the enteric pathogen Salmonella typhimurium via decreased NLRC4 inflammasome activation [6,25]. Intriguingly, the G2019S-LRRK2 mutation, which increases LRRK2 kinase activity, enhanced caspase-1 activation and IL-1β production in response to NLRC4 inflammasome activation in macrophages infected with S. typhimurium [25]. Similarly, knockout of Lrrk2 increases susceptibility to the oral infection to a different enteric pathogen, Listeria monocytogenes [26]. Similar antagonistic pleiotropic effects of the gain-of-kinase function G2019S mutation have recently been reported in models of sepsis and encephalitis [50]. It was observed that the G2019S mutation controlled infection better, with reduced bacterial growth and longer survival during sepsis; an effect which was dependent on myeloid cells and LRRK2 kinase activity. However, animals with reovirus-induced encephalitis that expressed the G2019S mutation exhibited increased mortality, increased reactive oxygen species and higher concentrations of α-synuclein in the brain. Such data implies potential opposing effects of LRRK2-mediated inflammation in the CNS versus the periphery. Collectively, these data point towards the potential of LRRK2 having pleiotropic effects on bacterial control and inflammation dependent on the bacterial infection (the concept of LRRK2 being a pleiotropic actor at both the genetic and molecular level has recently been reviewed [51]).

LRRK2 in inflammatory bowel disease

IBD is composed of two major subtypes; Crohn's disease (CD) and ulcerative colitis (UC). The two can be distinguished by the distribution of chronic inflammatory changes. UC is typically confined to the colon, whilst CD is known to affect both the ileum and colon, and is associated with deep, transmural inflammation. Patients with IBD have a 22% increased risk of PD compared with non-IBD individuals [52]. With regards to LRRK2, genetic variances and mutations in the LRRK2 gene have been demonstrated to increase the risk of developing PD in both CD [30] and UC [52] patients.

The role of LRRK2 kinase activity in IBD is still unclear. LRRK2 has been identified by GWAS as a major susceptibility gene for CD [53], and the gain-of-function variant, N2081D, has recently been identified and shown to increase the risk of CD two-fold in at-risk populations [27]. The G2019S mutation, which increases kinase activity, has been shown to be increased in CD patients in the Ashkenazi Jewish population [28]. Furthermore, the down-regulation of LRRK2 was previously shown to enhance the susceptibility to dextran sulfate sodium salt (DSS)-induced colitis [22], suggesting a loss of LRRK2 activity may increase the risk for inflammation in the gut. This is in agreement with increased expression in the secretory immunoglobulin A, IgA, observed in the intestines of Lrrk2 deficient mice [54]. IgA is produced by intestinal B cells and is a crucial factor for maintaining a healthy intestinal tract barrier in terms of pathogen elimination, and increased IgA has been reported in patients with IBD [55]. However, in a mouse model of DSS-induced colitis, overexpression of the Lrrk2 gene causes increased severity in colitis, which was ameliorated with LRRK2 kinase inhibitors [29]. From this data, it is still not clear if the role of LRRK2 in IBD is due to a loss- or gain-of-function. What is apparent, however, is that LRRK2 is crucial for normal inflammatory responses, and alterations in LRRK2 activity or expression levels can increase inflammation in the gut.

LRRK2 and Rab GTPases in immune cells

Many proteins have been reported to be directly regulated by LRRK2, however, the number of these that have been validated and replicated by numerous groups is small [56]. Recent studies have identified a subset of Rab GTPases, including Rab3, Rab5, Rab7, Rab8, Rab10, Rab12, Rab35, Rab39b, Rab43 and Rab7L1, as bona fide substrates of LRRK2 in cells [37,38,57,58].

Rab GTPases are key organizers of intracellular membrane trafficking and have been heavily implicated in a range of neurodegenerative diseases (reviewed in detail in [59]). Intracellular membrane trafficking and the immune function of cells are linked in multiple ways and this coordination is critical for dynamic and specialized immune defences. Interestingly, these specialized immune functions include phagocytosis and phagosome maturation, autophagy and antigen presentation [60], which have all been suggested to be regulated by LRRK2.

Phagocytosis is crucial for the clearance of dying cells and microbial pathogens. Proteomic studies have unveiled a network of Rab proteins that are associated with phagosomes and are highly essential for their maturation [61]. For example, Rab5 is present on early phagosomes where they regulate their fusion with early endosomes [61,62]. LRRK2 has been shown to form a complex with the protein WAVE2 (Wiskott–Aldrich syndrome protein-family verproline 2) and colocalize with Rab5a during phagosome-early endosome fusion in BMDMs [21]. Furthermore, G2019S-LRRK2 expression in these cells was shown to increase phagocytic activity, potentially due to altered Rab5a activity levels. This is in contrast with a report from Lrrk2-knockout (Lrrk2-KO) microglia, that showed increased uptake and clearance of α-synuclein with the loss of LRRK2 due to increases in Rab5 positive endosomes [18]. Thus, it seems that LRRK2 and its interacting partners may regulate phagocytosis in a cell-type-specific manner.

Rab7 is typically associated with late phagosomes and facilitates the fusion of these vesicles with lysosomes. Interestingly, many studies have demonstrated that PD-associated LRRK2 mutations have deleterious effects on Rab7 functions. For example, G2019S-LRRK2 decreases Rab7 activity, leading to decreased degradative receptor trafficking [63], and lysosomal defects can be rescued upon Rab7 inhibition in LRRK2-PD patient fibroblasts [64]. A recent study has suggested that LRRK2-mediated deficits in Rab7 function are not due to direct phosphorylation of Rab7, but rather via the interaction between LRRK2 and it's substrate, Rab8A [65]. Interestingly, Rab8A has been shown to modulate TLR4-dependent immune responses [66]. This signalling pathway has been shown to modulate phosphorylation of LRRK2 as well as its subsequent cellular localization, dimerization and translocation to membranes [20,67,68], suggesting a bi-directional regulatory effect of LRRK2 and its Rab substrates.

Rab10 is known to regulate phagosomal recycling [69] and has been shown to be phosphorylated in human peripheral blood mononuclear cells [70] and isolated human neutrophils [71] by LRRK2. Furthermore, both PD and CD-associated pathogenic mutations and risk variants increase phosphorylation of Rab10 at the amino acid residue threonine 73 in patient macrophages [27]. However, this increase in Rab10 phosphorylation was not replicated in patient neutrophils, suggesting a cell-type dependent effect of LRRK2-mediated Rab10 phosphorylation [15]. With regards to the functional effects of this interaction with Rab10, LRRK2 is recruited to the lysosome upon lysosomal overload stress, alongside Rab7L1, where it stabilizes Rab10 and Rab8 through phosphorylation [72]. Furthermore, knockout of Lrrk2 increases vacuolization and lipofuscin autofluorescence, indicating that LRRK2 may protect against lysosomal enlargement and up-regulates lysosomal secretion during lysosomal stress. These findings also suggest that under stress-conditions, phosphorylated Rab GTPases acquire novel functions from those under steady-state conditions. It has been suggested that the roles of Rab8 and Rab10 on stressed lysosomes are different from their physiological functions documented in recycling phagosomes [72].

Collectively, these data highlight the complex and pertinent role of the interaction between LRRK2 and Rab GTPases in immune cell homeostasis (Figure 1). It is clear from these reports that both LRRK2 and Rab GTPases are capable of regulating immune cell function in a cell-type-specific manner. Whether or not the interaction between LRRK2 and different Rab GTPases is also cell-type dependent, and dependent on stress-conditions or different immune challenges, is of high interest for future research.

Events downstream of LRRK2 in immune cells

Previous evidence has shown that LRRK2 is involved in numerous pathways, including transcription, mitochondrial function and neurotransmitter release. In the context of immune cells, however, two cellular pathways are of particular interest and will be reviewed in detail: immune signalling and autophagy.

LRRK2 and inflammatory signalling pathways

The mitogen-activated protein kinase pathways (MAPK) were among the first to be investigated as potentially relating to LRRK2. MAPK pathways comprise of three proteins situated in a cascade, with different subtypes leading to the activation of different effectors involved in a range of functions such as apoptosis and inflammation. LRRK2 has been shown to bind to and phosphorylate MAP2K-3, -4, -6 and -7 [73,74], with increased kinase activity leading to hyperphosphorylation and dopaminergic neuronal death [75]. More recently, it has been demonstrated that LRRK2 kinase activity plays a critical role in manganese-induced inflammation and toxicity via downstream activation of MAPK signalling in both macrophages and microglia [76].

As previously discussed, LRRK2 has been shown to inhibit responses to infection via the NRON complex [49]. Interestingly, the NRON complex inhibits NFAT1 transcription, which modulates cytokine expression. LRRK2 has been shown to negatively modulate NFAT1 translocation to the nucleus, with LRRK2 deficiency conferring enhanced susceptibility to experimentally induced colitis in mice due to increased inflammation [22], highlighting converging LRRK2-mediated mechanisms between diseases.

LRRK2 has also been heavily implicated in NF-κB signalling. A recent transcriptomics study revealed that microglia from Lrrk2-KO mice exhibit a decreased inflammatory response with LPS or α-synuclein pre-formed fibril (PFF) treatment [77]. Interestingly, the NF-κB transcriptional regulator, NFKBIZ, was significantly decreased in Lrrk2-KO microglia in response to α-synuclein PFF. This is in agreement with previously reported findings from Lrrk2-KO microglia, where increases in the inhibitory p50 homodimer was observed, leading to an attenuated inflammatory response [19]. This was shown to be a downstream consequence of increased PKA activity, known to be negatively regulated by LRRK2 [78]. It has also been observed that LRRK2 lies downstream of the β-glucan receptor, Dectin-1, leading to activation of the NF-κB components TAK1 complex and TRAF6, increasing pro-inflammatory cytokine secretion [29]. Interestingly, Dectin-1 receptor signalling is also known to induce the LRRK2-associated NFAT signalling pathway [79]. As well, LRRK2 has recently been shown to phosphorylate RCAN1, a protein inhibitor of calcineurin, the main activator of NFAT transcriptional responses, leading to the increased transcriptional activity of NF-κB and IL-8 production [80].

Collectively, this data on LRRK2 in MAPK, NFAT1 NF-κB and RCAN1 signalling highlights that LRRK2 is situated downstream of multiple affecters and can regulate multiple inflammatory pathways via different mechanisms (Figure 2).

LRRK2, autophagy and the lysosome in immune cells

The degradative pathway of autophagy plays a crucial role in regulating different aspects of the innate and adaptive immune systems and is intrinsically linked to phagocytosis due to the convergence of both pathways on the lysosome (Figure 1). Furthermore, due to its role in the maintenance of biological homeostasis in conditions of stress, dysregulation or disruption of autophagy has been linked to IBD [81], PD [82,83] and host defence of Mtb [84] and other bacterial infections [85]. The macroautophagy pathway (hereby referred to as autophagy) arises from the formation of a phagophore that engulfs cargo for degradation and encloses to become an autophagosome. The autophagosome will then fuse with a lysosome to form mature autolysosome at which point contents can be degraded.

LRRK2 was first shown to regulate autophagy specifically in immune cells in 2014 where LPS-stimulation of monocytic cell lines increased LRRK2 translocation to autophagosome membrane, with loss of LRRK2 leading to autophagic deficits [67]. Furthermore, it has recently been demonstrated in a mouse macrophage cell line that, upon lysosomal overload stress, LRRK2 is recruited to the lysosome, alongside Rab7L1, where it stabilizes Rab8 and Rab10 through phosphorylation [72]. In the same study, it was also shown that the knockout of Lrrk2 increases vacuolization and lipofuscin autofluorescence, indicating that LRRK2 may protect against lysosomal enlargement and up-regulates lysosomal secretion during lysosomal stress in immune cells.

Collectively, this data suggests LRRK2 is functionally beneficial for the autophagy pathway. However, there are contradictions in the literature. For example, Lrrk2 overexpression in mouse bone-marrow-derived dendritic cells causes inhibition of autophagy via Beclin-1 inactivation [29]. This Beclin-1 mediated inhibition of autophagy by LRRK2 has previously been reported in astrocytes [86]. One consequence of autophagy inhibition mediated by LRRK2 signalling is that it leads to increased LRRK2 [29] and therefore may further exacerbate LRRK2-mediated inflammation. Interestingly, there is evidence that NF-κB can inhibit autophagy via the up-regulation of NEDD4, a signalling component that can cause Beclin-1 cleavage as does LRRK2 [87]. NF-κB activation and autophagy, therefore, have reciprocal effects on each other; whether the effects of LRRK2 on these pathways are independent or linked is currently unknown and will be of interest to future research.

Autophagy is now one of the most intensively studied pathways in the LRRK2 field, however, many aspects are still not fully understood, and results often conflicting. Discrepancies in the literature may be a result from the use of different cell types used in this research (Table 2). The ‘date-hub’ hypothesis describes two types of ‘hubs’ in protein interaction networks; ‘party hubs’, which interact with most of their partners simultaneously at the same time and space, and ‘date hubs’, which bind their different partners at different times or locations. The potential for LRRK2 behaving as a ‘date-hub’ has been discussed in the literature [88] and may explain the discrepancies reported. Under the perspective of the date-hub hypothesis, LRRK2 may be capable of interacting with different proteins. Therefore, LRRK2 could control different cellular pathways (or modulate the same pathway differentially) based on the expression of LRRK2 activators and partners and the complexes formed in a cell-type-specific manner. Furthermore, it is noticeable that, although autophagy is an intensively studied pathway regarding LRRK2, only a small proportion of those studies has been carried out in immune cells. As well, despite the crucial role autophagy and the lysosome play in regulating different aspects of the innate and adaptive immune systems, mechanistic insight into how LRRK2's role in autophagy and lysosome function impacts inflammatory pathways in immune cells remains unknown, and is an important area for further research.

Concluding remarks

Research over the last decade has increased our understanding of the pathophysiological role of LRRK2 in disease and supports the role of LRRK2 in inflammation and immune cell function. Rab GTPases have been identified as bona fide LRRK2 substrates, and LRRK2 regulates phagocytosis, cell-signalling and autophagy in immune cells. What is apparent from the current literature regarding leprosy, bacterial infection and PD, is a distinct role of LRRK2 in inflammation in a cell-specific manner. Interestingly, Rab GTPases in immune cells are recruited differentially to phagosomes and other cellular organelles based on cell-type and extracellular stimuli [114,115]. Given the important role of Rab GTPases in LRRK2 function and in immune cell function, more research is required in order to unequivocally establish the bona fide interacting partners of LRRK2 in different immune cell types under different conditions. Furthermore, additional research is required in order to establish the involvement of LRRK2 in inflammatory pathways in different immune cell types. Specifically, further research is required to unveil the cell-type dependent manner in which LRRK2 kinase activity regulates these different cellular pathways. LRRK2 kinase inhibitors have been discussed for their potential therapeutic effects in diseases such as PD where aberrant LRRK2 kinase activity is apparent. However, a loss of LRRK2 kinase activity may lead to an increased risk of infection and inflammation in the periphery, as suggested by data discussed here. Therefore, such malignant side effects would need to be taken into consideration if such inhibitors were to be therapeutically beneficial.

Understandably, a large percentage of the research aiming to understand LRRK2 enzymatic function has focused on its kinase activity. Kinases are appealing drug targets for pharmaceutical companies due to the fact that these enzymes are considered highly druggable and can be targeted by small-molecule chemistry. However, this also means that there is still uncertainty about the contribution of GTPase activity to cellular toxicity in immune cells. Although many model organisms with interesting phenotypes have been developed based upon familial mutations in the GTPase domain of LRRK2, mechanistic insight into the contribution of GTPase activity is so far lacking [116]. As well, it is important to consider that the enzymatic core of LRRK2 is surrounded by protein–protein interaction domains, which have received considerably less research attention over the last decade. The G2385R mutation, which is located in the WD40 domain of LRRK2, is a risk factor for PD [117], emphasizing the need for future research on the role of these protein–protein interaction domains in disease. Understanding how LRRK2 GTPase activity and its role as a scaffolding protein contributes to such phenotypes in immune cells will be challenging and may rely in the future upon genetic or pharmacological manipulations.

Perspectives

  • LRRK2 has been implicated in multiple processes critical for immune cell function. Unveiling pathological mechanisms of mutations in immune cells is of great importance for research on PD, IBD and bacterial infections

  • LRRK2 can regulate inflammatory pathways in multiple cell types via different mechanisms. The current literature highlights the pertinent role of the interaction between LRRK2 and Rab GTPases in immune cell homeostasis.

  • Discrepancies in the literature highlight cell-type dependent effects of LRRK2 on immune cell function. Future research will benefit from a direct comparison between immune cells and identifying bona fide substrates of LRRK2 in different cell types and under different immune conditions.

Abbreviations

     
  • BMDMs

    bone-marrow-derived macrophages

  •  
  • CD

    Crohn's disease

  •  
  • CNS

    central nervous system

  •  
  • DEG

    differentially expressed gene

  •  
  • DSS

    extran sulfate sodium salt

  •  
  • HUVECs

    human umbilical vein endothelial cells

  •  
  • IBD

    inflammatory bowel disease

  •  
  • IFN-γ

    interferon-γ

  •  
  • LPS

    lipopolysaccharide

  •  
  • LRR

    leucine-rich-repeat

  •  
  • LRRK2

    leucine-rich-repeat kinase 2

  •  
  • Lrrk2-KO

    Lrrk2-knockout

  •  
  • MAPK

    mitogen-activated protein kinase pathways

  •  
  • Mtb

    Mycobacterium tuberculosis

  •  
  • PBMCs

    peripheral blood mononuclear cells

  •  
  • PD

    Parkinson's disease

  •  
  • PFF

    pre-formed fibril

  •  
  • PI3K

    phosphatidylinositol-3 kinase

  •  
  • ROS

    reactive oxygen species

  •  
  • SNPs

    single nucleotide polymorphisms

  •  
  • T1R

    type-1 reactions

  •  
  • TB

    tuberculosis

  •  
  • TLR4

    toll-like receptor 4

  •  
  • UC

    ulcerative colitis

  •  
  • WAVE2

    Wiskott–Aldrich syndrome protein-family verproline 2

  •  
  • WT

    wild-type

Funding

The Michael J. Fox Foundation for Parkinson's Research, the Parkinson's Foundation and the National Institutes of Health (NIH) grants [1R01NS092122, 1RF1AG057247, 1RF1AG051514] for funding support for R.L.W. and M.G.T.

Acknowledgements

We thank Mary K. Herrick and other members of the Tansey laboratory for useful discussions.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

References

References
1
Rudenko
,
I.N.
,
Chia
,
R.
and
Cookson
,
M.R.
(
2012
)
Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?
BMC Med.
10
,
20
2
Singleton
,
A.B.
,
Farrer
,
M.J.
and
Bonifati
,
V.
(
2013
)
The genetics of Parkinson's disease: progress and therapeutic implications
.
Mov. Disord.
28
,
14
23
3
Lee
,
H.
,
James
,
W.S.
and
Cowley
,
S.A.
(
2017
)
LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson's disease
.
Biochem. Soc. Trans.
45
,
131
139
4
Pross
,
S
. (
2007
) T cell activation, In
Reference Module in Biomedical Sciences
(Enna, S.J. and David, B.N., eds.), pp.
1
-
7
,
Elsevier, USA
5
Mukherjee
,
R.
,
Kanti Barman
,
P.
,
Kumar Thatoi
,
P.
,
Tripathy
,
R.
,
Kumar Das
,
B.
and
Ravindran
,
B.
(
2015
)
Non-classical monocytes display inflammatory features: validation in sepsis and systemic lupus erythematous
.
Sci. Rep.
5
,
5577
5585
6
Gardet
,
A.
,
Benita
,
Y.
,
Li
,
C.
,
Sands
,
B.E.
,
Ballester
,
I.
,
Stevens
,
C.
et al (
2010
)
LRRK2 is involved in the IFN-response and host response to pathogens
.
J. Immunol.
185
,
5577
5585
7
Cook
,
D.A.
,
Kannarkat
,
G.T.
,
Cintron
,
A.F.
,
Butkovich
,
L.M.
,
Fraser
,
K.B.
,
Chang
,
J.
et al (
2017
)
LRRK2 levels in immune cells are increased in Parkinson's disease
.
NPJ Parkinson's Dis.
3
,
11
8
Thévenet
,
J.
,
Pescini Gobert
,
R.
,
Hooft van Huijsduijnen
,
R.
,
Wiessner
,
C.
,
Sagot
,
Y.J.
and
Sozzani
,
S.
(
2011
)
Regulation of LRRK2 expression points to a functional role in human monocyte maturation
.
PLoS One
6
,
e21519
.
9
Kuss
,
M.
,
Adamopoulou
,
E.
and
Kahle
,
P.J.
(
2014
)
Interferon-gamma induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages
.
J. Neurochem.
129
,
980
987
10
Hakimi
,
M.
,
Selvanantham
,
T.
,
Swinton
,
E.
,
Padmore
,
R.F.
,
Tong
,
Y.
,
Kabbach
,
G.
et al (
2011
)
Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures
.
J. Neural. Transm. (Vienna)
118
,
795
808
11
Moehle
,
M.S.
,
Webber
,
P.J.
,
Tse
,
T.
,
Sukar
,
N.
,
Standaert
,
D.G.
,
DeSilva
,
T.M.
et al (
2012
)
LRRK2 inhibition attenuates microglial inflammatory responses
.
J. Neurosci.
32
,
1602
1611
12
Hongge
,
L.
,
Kexin
,
G.
,
Xiaojie
,
M.
,
Nian
,
X.
and
Jinsha
,
H.
(
2015
)
The role of LRRK2 in the regulation of monocyte adhesion to endothelial cells
.
J. Mol. Neurosci.
55
,
233
239
13
Gillardon
,
F.
,
Schmid
,
R.
and
Draheim
,
H.
(
2012
)
Parkinson's disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity
.
Neuroscience
208
,
41
48
14
Daher
,
J.P.
,
Volpicelli-Daley
,
L.A.
,
Blackburn
,
J.P.
,
Moehle
,
M.S.
and
West
,
A.B.
(
2014
)
Abrogation of alpha-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats
.
Proc. Natl. Acad. Sci. U.S.A.
111
,
9289
9294
15
Atashrazm
,
F.
,
Hammond
,
D.
,
Perera
,
G.
,
Bolliger
,
M.F.
,
Matar
,
E.
,
Halliday
,
G.M.
et al (
2019
)
LRRK2-mediated rab10 phosphorylation in immune cells from Parkinson's disease patients
.
Mov. Disord.
34
,
406
415
16
Dzamko
,
N.
,
Rowe
,
D.B.
and
Halliday
,
G.M.
(
2016
)
Increased peripheral inflammation in asymptomatic leucine-rich repeat kinase 2 mutation carriers
.
Mov. Disord.
31
,
889
897
17
Kozina
,
E.
,
Sadasivan
,
S.
,
Jiao
,
Y.
,
Dou
,
Y.
,
Ma
,
Z.
,
Tan
,
H.
et al (
2018
)
Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo
.
Brain
141
,
1753
1769
18
Maekawa
,
T.
,
Sasaoka
,
T.
,
Azuma
,
S.
,
Ichikawa
,
T.
,
Melrose
,
H.L.
,
Farrer
,
M.J.
et al (
2016
)
Leucine-rich repeat kinase 2 (LRRK2) regulates α-synuclein clearance in microglia
.
BMC Neurosci.
17
,
77
19
Russo
,
I.
,
Berti
,
G.
,
Plotegher
,
N.
,
Bernardo
,
G.
,
Filograna
,
R.
,
Bubacco
,
L.
et al (
2015
)
Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-κB p50 signaling in cultured microglia cells
.
J. Neuroinflammation
12
,
230
20
Dzamko
,
N.
,
Inesta-Vaquera
,
F.
,
Zhang
,
J.
,
Xie
,
C.
,
Cai
,
H.
,
Arthur
,
S.
et al (
2012
)
The ikappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during toll-like receptor signaling
.
PLoS One
7
,
e39132
21
Kim
,
K.S.
,
Marcogliese
,
P.C.
,
Yang
,
J.
,
Callaghan
,
S.M.
,
Resende
,
V.
,
Abdel-Messih
,
E.
et al (
2018
)
Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson's disease
.
Proc. Natl. Acad. Sci. U.S.A.
115
,
E5164
E5173
22
Liu
,
Z.
,
Lee
,
J.
,
Krummey
,
S.
,
Lu
,
W.
,
Cai
,
H.
and
Lenardo
,
M.J.
(
2011
)
The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
.
Nat. Immunol.
12
,
1063
1070
23
Fava
,
V.M.
,
Xu
,
Y.Z.
,
Lettre
,
G.
,
Van Thuc
,
N.
,
Orlova
,
M.
,
Thai
,
V.H.
et al (
2019
)
Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease
.
Proc. Natl. Acad. Sci. U.S.A.
116
,
15616
15624
24
Härtlova
,
A.
,
Herbst
,
S.
,
Peltier
,
J.
,
Rodgers
,
A.
,
Bilkei-Gorzo
,
O.
,
Fearns
,
A.
et al (
2018
)
LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
.
EMBO J.
37
,
e98694
25
Liu
,
W.
,
Liu
,
X.
,
Li
,
Y.
,
Zhao
,
J.
,
Liu
,
Z.
,
Hu
,
Z.
et al (
2017
)
LRRK2 promotes the activation of NLRC4 inflammasome during Salmonella typhimurium infection
.
J. Exp. Med.
214
,
3051
3066
26
Zhang
,
Q.
,
Pan
,
Y.
,
Yan
,
R.
,
Zeng
,
B.
,
Wang
,
H.
,
Zhang
,
X.
et al (
2015
)
Commensal bacteria direct selective cargo sorting to promote symbiosis
.
Nat. Immunol.
16
,
918
926
27
Hui
,
K.Y.
,
Fernandez-Hernandez
,
H.
,
Hu
,
J.
,
Schaffner
,
A.
,
Pankratz
,
N.
,
Hsu
,
N.Y.
et al (
2018
)
Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease
.
Sci. Transl. Med.
10
,
eaai7795
28
Rivas
,
M.A.
,
Avila
,
B.E.
,
Koskela
,
J.
,
Huang
,
H.
,
Stevens
,
C.
,
Pirinen
,
M.
et al (
2019
)
Correction: insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population
.
PLOS Genet.
15
,
e1008190
29
Takagawa
,
T.
,
Kitani
,
A.
,
Fuss
,
I.
,
Levine
,
B.
,
Brant
,
S.R.
,
Peter
,
I.
et al (
2018
)
An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis
.
Sci. Transl. Med.
10
,
eaan8162
30
Witoelar
,
A.
,
Jansen
,
I.E.
Wang
,
Y.
,
Desikan
,
R.S.
,
Gibbs
,
J.R.
,
Blauwendraat
,
C.
et al (
2017
)
Genome-wide pleiotropy between Parkinson disease and autoimmune diseases
.
JAMA Neurol.
74
,
780
31
Covy
,
J.P.
and
Giasson
,
B.I.
(
2009
)
Identification of compounds that inhibit the kinase activity of leucine-rich repeat kinase 2
.
Biochem. Biophys. Res. Commun.
378
,
473
477
32
Luzón-Toro
,
B.
,
de la Torre E
,
R.
,
Delgado
,
A.
,
Pérez-Tur
,
J.
and
Hilfiker
,
S.
(
2007
)
Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation
.
Hum. Mol. Genet.
16
,
2031
2039
33
West
,
A.B.
,
Moore
,
D.J.
,
Biskup
,
S.
,
Bugayenko
,
A.
,
Smith
,
W.W.
,
Ross
,
C.A.
et al (
2005
)
From the cover: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity
.
Proc. Natl. Acad. Sci. U.S.A.
102
,
16842
16847
34
Anand
,
V.S.
and
Braithwaite
,
S.P.
(
2009
)
LRRK2 in Parkinson's disease: biochemical functions
.
FEBS J.
276
,
6428
6435
35
Smith
,
W.W.
,
Pei
,
Z.
,
Jiang
,
H.
,
Dawson
,
V.L.
,
Dawson
,
T.M.
and
Ross
,
C.A.
(
2006
)
Kinase activity of mutant LRRK2 mediates neuronal toxicity
.
Nat. Neurosci.
9
,
1231
1233
36
West
,
A.B.
,
Moore
,
D.J.
,
Choi
,
C.
,
Andrabi
,
S.A.
,
Li
,
X.
,
Dikeman
,
D.
et al (
2007
)
Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity
.
Hum. Mol. Genet.
16
,
223
232
37
Steger
,
M.
,
Diez
,
F.
,
Dhekne
,
H.S.
,
Lis
,
P.
,
Nirujogi
,
R.S.
,
Karayel
,
O.
et al (
2017
)
Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis
.
eLife
6
,
e31012
38
Liu
,
Z.
,
Bryant
,
N.
,
Kumaran
,
R.
,
Beilina
,
A.
,
Abeliovich
,
A.
,
Cookson
,
M.R.
et al (
2018
)
LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network
.
Hum. Mol. Genet.
27
,
385
395
39
Lewis
,
P.A.
,
Greggio
,
E.
,
Beilina
,
A.
,
Jain
,
S.
,
Baker
,
A.
and
Cookson
,
M.R.
(
2007
)
The R1441C mutation of LRRK2 disrupts GTP hydrolysis
.
Biochem. Biophys. Res. Commun.
357
,
668
671
40
Wang
,
D.
,
Xu
,
L.
,
Lv
,
L.
,
Su
,
L.-Y.
,
Fan
,
Y.
,
Zhang
,
D.-F.
et al (
2015
)
Association of the LRRK2 genetic polymorphisms with leprosy in Han Chinese from Southwest China
.
Genes Immun.
16
,
112
119
41
Wong
,
S.H.
(
2010
)
Genomewide association study of leprosy
.
N. Engl. J. Med.
362
,
1446
1448
42
Grant
,
A.V.
,
Alter
,
A.
,
Huong
,
N.T.
,
Orlova
,
M.
,
Van Thuc
,
N.
,
Ba
,
N.N.
et al (
2012
)
Crohn's disease susceptibility genes are associated with leprosy in the Vietnamese population
.
J. Infect. Dis.
206
,
1763
1767
43
Marcinek
,
P.
,
Jha
,
A.N.
,
Shinde
,
V.
,
Sundaramoorthy
,
A.
,
Rajkumar
,
R.
,
Suryadevara
,
N.C.
et al (
2013
)
LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations
.
PLoS One
8
,
e73103
44
Fava
,
V.
,
Orlova
,
M.
,
Cobat
,
A.
,
Alcaïs
,
A.
,
Mira
,
M.
and
Schurr
,
E.
(
2012
)
Genetics of leprosy reactions: an overview
.
Mem. Inst. Oswaldo Cruz
107
,
132
142
45
Fava
,
V.M.
,
Manry
,
J.
,
Cobat
,
A.
,
Orlova
,
M.
,
Van Thuc
,
N.
,
Ba
,
N.N.
et al (
2016
)
A missense LRRK2 variant is a risk factor for excessive inflammatory responses in leprosy
.
PLoS Negl. Trop. Dis.
10
,
e0004412
46
Bagh
,
M.B.
,
Peng
,
S.
,
Chandra
,
G.
,
Zhang
,
Z.
,
Singh
,
S.P.
,
Pattabiraman
,
N.
et al (
2017
)
Misrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model
.
Nat. Commun.
8
,
14612
47
Zhang
,
L.
,
Wang
,
K.
,
Lei
,
Y.
,
Li
,
Q.
,
Nice
,
E.C.
and
Huang
,
C.
(
2015
)
Redox signaling: potential arbitrator of autophagy and apoptosis in therapeutic response
.
Free Radic. Biol. Med.
89
,
452
465
48
Yang
,
Y.
,
Jiang
,
G.
,
Zhang
,
P.
and
Fan
,
J.
(
2015
)
Programmed cell death and its role in inflammation
.
Mil. Med. Res.
2
,
12
49
Wang
,
Z.
,
Arat
,
S.
,
Magid-Slav
,
M.
and
Brown
,
J.R.
(
2018
)
Meta-analysis of human gene expression in response to Mycobacterium tuberculosis infection reveals potential therapeutic targets
.
BMC Syst. Biol.
12
,
3
50
Shutinoski
,
B.
,
Hakimi
,
M.
,
Harmsen
,
I.E.
Lunn
,
M.
,
Rocha
,
J.
,
Lengacher
,
N.
et al (
2019
)
Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner
.
Sci. Transl. Med.
11
,
eaas9292
51
Lewis
,
P.A.
(
2019
)
Leucine rich repeat kinase 2: a paradigm for pleiotropy
.
J. Physiol.
597
,
3511
3521
52
Villumsen
,
M.
,
Aznar
,
S.
,
Pakkenberg
,
B.
,
Jess
,
T.
and
Brudek
,
T.
(
2019
)
Inflammatory bowel disease increases the risk of Parkinson's disease: a Danish nationwide cohort study 1977–2014
.
Gut
68
,
18
24
53
Liu
,
J.Z.
,
van Sommeren
,
S.
,
Huang
,
H.
,
Ng
,
S.C.
,
Alberts
,
R.
,
Takahashi
,
A.
et al (
2015
)
Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations
.
Nat. Genet.
47
,
979
986
54
Maekawa
,
T.
,
Shimayama
,
H.
,
Tsushima
,
H.
,
Kawakami
,
F.
,
Kawashima
,
R.
,
Kubo
,
M.
et al (
2017
)
LRRK2: an emerging new molecule in the enteric neuronal system that quantitatively regulates neuronal peptides and IgA in the Gut
.
Dig. Dis. Sci.
62
,
903
912
55
Lin
,
R.
,
Chen
,
H.
,
Shu
,
W.
,
Sun
,
M.
,
Fang
,
L.
,
Shi
,
Y.
et al (
2018
)
Clinical significance of soluble immunoglobulins A and G and their coated bacteria in feces of patients with inflammatory bowel disease
.
J. Transl. Med.
16
,
359
56
Price
,
A.
,
Manzoni
,
C.
,
Cookson
,
M.R.
and
Lewis
,
P.A.
(
2018
)
The LRRK2 signalling system
.
Cell Tissue Res.
373
,
39
50
57
Steger
,
M.
,
Tonelli
,
F.
,
Ito
,
G.
,
Davies
,
P.
,
Trost
,
M.
,
Vetter
,
M.
et al (
2016
)
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
.
eLife
5
,
e12813
58
Fujimoto
,
T.
,
Kuwahara
,
T.
,
Eguchi
,
T.
,
Sakurai
,
M.
,
Komori
,
T.
and
Iwatsubo
,
T.
(
2018
)
Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology
.
Biochem. Biophys. Res. Commun.
495
,
1708
1715
59
Kiral
,
F.R.
,
Kohrs
,
F.E.
,
Jin
,
E.J.
and
Hiesinger
,
P.R.
(
2018
)
Rab GTPases and membrane trafficking in neurodegeneration
.
Curr. Biol.
28
,
R471
R486
60
Prashar
,
A.
,
Schnettger
,
L.
,
Bernard
,
E.M.
and
Gutierrez
,
M.G.
(
2017
)
Rab GTPases in immunity and inflammation
.
Front. Cell Infect. Microbiol
7
,
435
61
Gutierrez
,
M.G.
(
2013
)
Functional role(s) of phagosomal Rab GTPases
.
Small GTPases
4
,
148
158
62
Yeo
,
J.C.
,
Wall
,
A.A.
,
Luo
,
L.
and
Stow
,
J.L.
(
2016
)
Sequential recruitment of Rab GTPases during early stages of phagocytosis
.
Cell Logist.
6
,
e1140615
63
Gómez-Suaga
,
P.
,
Rivero-Ríos
,
P.
,
Fdez
,
E.
,
Blanca Ramírez
,
M.
,
Ferrer
,
I.
,
Aiastui
,
A.
et al (
2014
)
LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity
.
Hum. Mol. Genet.
23
,
6779
6796
64
Hockey
,
L.N.
,
Kilpatrick
,
B.S.
,
Eden
,
E.R.
,
Lin-Moshier
,
Y.
,
Brailoiu
,
G.C.
,
Brailoiu
,
E.
et al (
2015
)
Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition
.
J. Cell Sci.
128
,
232
238
65
Rivero-Ríos
,
P.
,
Romo-Lozano
,
M.
,
Madero-Pérez
,
J.
,
Thomas
,
A.P.
,
Biosa
,
A.
,
Greggio
,
E.
et al (
2019
)
The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A
.
J. Biol. Chem.
294
,
4738
4758
66
Luo
,
L.
,
Wall
,
A.A.
,
Yeo
,
J.C.
,
Condon
,
N.D.
,
Norwood
,
S.J.
,
Schoenwaelder
,
S.
et al (
2014
)
Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling
.
Nat. Commun.
5
,
4407
67
Schapansky
,
J.
,
Nardozzi
,
J.D.
,
Felizia
,
F.
and
LaVoie
,
M.J.
(
2014
)
Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy
.
Hum. Mol. Genet.
23
,
4201
4214
68
Moehle
,
M.S.
,
Daher
,
J.P.L.
,
Hull
,
T.D.
,
Boddu
,
R.
,
Abdelmotilib
,
H.A.
,
Mobley
,
J.
et al (
2015
)
The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins
.
Hum. Mol. Genet.
24
,
4250
4267
69
Chua
,
C.E.L.
and
Tang
,
B.L.
(
2018
)
Rab 10-a traffic controller in multiple cellular pathways and locations
.
J. Cell. Physiol.
233
,
6483
6494
70
Thirstrup
,
K.
,
Dächsel
,
J.C.
,
Oppermann
,
F.S.
,
Williamson
,
D.S.
,
Smith
,
G.P.
,
Fog
,
K.
et al (
2017
)
Selective LRRK2 kinase inhibition reduces phosphorylation of endogenous Rab10 and Rab12 in human peripheral mononuclear blood cells
.
Sci. Rep.
7
,
10300
71
Fan
,
Y.
,
Howden
,
A.J.M.
,
Sarhan
,
A.R.
,
Lis
,
P.
,
Ito
,
G.
,
Martinez
,
T.N.
et al (
2018
)
Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils
.
Biochem. J.
475
,
23
44
72
Eguchi
,
T.
,
Kuwahara
,
T.
,
Sakurai
,
M.
,
Komori
,
T.
,
Fujimoto
,
T.
,
Ito
,
G.
et al (
2018
)
LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis
.
Proc. Natl. Acad. Sci. U.S.A.
115
,
E9115
E9124
73
Hsu
,
C.H.
,
Chan
,
D.
,
Greggio
,
E.
,
Saha
,
S.
,
Guillily
,
M.D.
,
Ferree
,
A.
et al (
2010
)
MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2
.
J. Neurochem.
112
,
1593
1604
74
Gloeckner
,
C.J.
,
Schumacher
,
A.
,
Boldt
,
K.
and
Ueffing
,
M.
(
2009
)
The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro
.
J. Neurochem.
109
,
959
968
75
Chen
,
C.-Y.
,
Weng
,
Y.-H.
,
Chien
,
K.-Y.
,
Lin
,
K.-J.
,
Yeh
,
T.-H.
,
Cheng
,
Y.-P.
et al (
2012
)
(G2019s) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD
.
Cell Death Differ.
19
,
1623
1633
76
Kim
,
J.
,
Pajarillo
,
E.
,
Rizor
,
A.
,
Son
,
D.-S.
,
Lee
,
J.
,
Aschner
,
M.
et al (
2019
)
LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia
.
PLoS One
14
,
e0210248
77
Russo
,
I.
,
Kaganovich
,
A.
,
Ding
,
J.
,
Landeck
,
N.
,
Mamais
,
A.
,
Varanita
,
T.
et al (
2019
)
Transcriptome analysis of LRRK2 knock-out microglia cells reveals alterations of inflammatory- and oxidative stress-related pathways upon treatment with alpha-synuclein fibrils
.
Neurobiol. Dis.
129
,
67
78
78
Parisiadou
,
L.
,
Yu
,
J.
,
Sgobio
,
C.
,
Xie
,
C.
,
Liu
,
G.
,
Sun
,
L.
et al (
2014
)
LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity
.
Nat. Neurosci.
17
,
367
376
79
Fric
,
J.
,
Zelante
,
T.
,
Wong
,
A.Y.W.
,
Mertes
,
A.
,
Yu
,
H.-B.
and
Ricciardi-Castagnoli
,
P.
(
2012
)
NFAT control of innate immunity
.
Blood
120
,
1380
1389
80
Han
,
K.A.
,
Yoo
,
L.
,
Sung
,
J.Y.
,
Chung
,
S.A.
,
Um
,
J.W.
,
Kim
,
H.
et al (
2017
)
Leucine-Rich repeat kinase 2 (LRRK2) stimulates IL-1beta-mediated inflammatory signaling through phosphorylation of RCAN1
.
Front. Cell. Neurosci.
11
,
125
81
Kim
,
S.
,
Eun
,
H.
and
Jo
,
E.-K.
(
2019
)
Roles of autophagy-related genes in the pathogenesis of inflammatory bowel disease
.
Cells
8
,
77
82
Wallings
,
R.
,
Manzoni
,
C.
and
Bandopadhyay
,
R.
(
2015
)
Cellular processes associated with LRRK2 function and dysfunction
.
FEBS J.
282
,
2806
2826
83
Gan-Or
,
Z.
,
Dion
,
P.A.
and
Rouleau
,
G.A.
(
2015
)
Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease
.
Autophagy
11
,
1443
1457
84
Lam
,
A.
,
Prabhu
,
R.
,
Gross
,
C.M.
,
Riesenberg
,
L.A.
,
Singh
,
V.
and
Aggarwal
,
S.
(
2017
)
Role of apoptosis and autophagy in tuberculosis
.
Am. J. Physiol. Lung Cell. Mol. Physiol.
313
,
L218
L229
85
Bah
,
A.
,
Vergne
,
I.
,
Autophagy
,
M.
,
Infections
,
B.
and
Immunol
,
F.
(
2017
)
Macrophage autophagy and bacterial infections
.
Front. Immunol.
1483
,
8
86
Manzoni
,
C.
,
Mamais
,
A.
,
Roosen
,
D.A.
,
Dihanich
,
S.
,
Soutar
,
M.P.M.
,
Plun-Favreau
,
H.
et al (
2016
)
mTOR independent regulation of macroautophagy by leucine rich repeat kinase 2 via Beclin-1
6
,
35106
87
Platta
,
H.W.
,
Abrahamsen
,
H.
,
Thoresen
,
S.B.
and
Stenmark
,
H.
(
2012
)
Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1
.
Biochem. J.
441
,
399
406
88
Manzoni
,
C.
(
2017
)
The LRRK2-macroautophagy axis and its relevance to Parkinson's disease
.
Biochem. Soc. Trans.
45
,
155
162
89
Plowey
,
E.D.
,
Cherra
,
S.J.
,
Liu
,
Y.-J.
and
Chu
,
C.T.
(
2008
)
Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells
.
J. Neurochem.
105
,
1048
1056
90
Alegre-Abarrategui
,
J.
,
Christian
,
H.
,
Lufino
,
M.M.
,
Mutihac
,
R.
,
Venda
,
L.L.
,
Ansorge
,
O.
et al (
2009
)
LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model
.
Hum. Mol. Genet.
18
,
4022
4034
91
Gómez-Suaga
,
P.
,
Luzón-Toro
,
B.
,
Churamani
,
D.
,
Zhang
,
L.
,
Bloor-Young
,
D.
,
Patel
,
S.
et al (
2012
)
Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP
.
Hum. Mol. Genet.
21
,
511
525
92
Sánchez-Danés
,
A.
,
Richaud-Patin
,
Y.
,
Carballo-Carbajal
,
I.
,
Jiménez-Delgado
,
S.
,
Caig
,
C.
,
Mora
,
S.
et al (
2012
)
Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
.
EMBO Mol. Med.
4
,
380
395
93
Bravo-San Pedro
,
J.M.
,
Niso-Santano
,
M.
,
Gómez-Sánchez
,
R.
,
Pizarro-Estrella
,
E.
,
Aiastui-Pujana
,
A.
,
Gorostidi
,
A.
et al (
2013
)
The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway
.
Cell. Mol. Life Sci.
70
,
121
136
94
Manzoni
,
C.
,
Mamais
,
A.
,
Dihanich
,
S.
,
McGoldrick
,
P.
,
Devine
,
M.J.
,
Zerle
,
J.
et al (
2013
)
Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation
.
Biochem. Biophys. Res. Commun.
441
,
862
866
95
Su
,
Y.C.
and
Qi
,
X.
(
2013
)
Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation
.
Hum. Mol. Genet.
22
,
4545
4561
96
Saez-Atienzar
,
S.
,
Bonet-Ponce
,
L.
,
Blesa
,
J.R.
,
Romero
,
F.J.
,
Murphy
,
M.P.
,
Jordan
,
J.
et al (
2014
)
The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling
.
Cell Death Dis.
5
,
e1368
97
Saha
,
S.
,
Liu-Yesucevitz
,
L.
and
Wolozin
,
B.
(
2014
)
Regulation of autophagy by LRRK2 in Caenorhabditis elegans
.
Neurodegener. Dis.
13
,
110
113
98
Su
,
Y.-C.
,
Guo
,
X.
and
Qi
,
X.
(
2015
)
Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy
.
Biochim. Biophys. Acta
1852
,
12
21
99
Henry
,
A.G.
,
Aghamohammadzadeh
,
S.
,
Samaroo
,
H.
,
Chen
,
Y.
,
Mou
,
K.
,
Needle
,
E.
et al (
2015
)
Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression
.
Hum. Mol. Genet.
24
,
6013
6028
100
Manzoni
,
C.
,
Mamais
,
A.
,
Dihanich
,
S.
,
Abeti
,
R.
,
Soutar
,
M.P.M.
,
Plun-Favreau
,
H.
et al (
2013
)
Inhibition of LRRK2 kinase activity stimulates macroautophagy
.
Biochim. Biophys. Acta
1833
,
2900
2910
101
Park
,
S.
,
Han
,
S.
,
Choi
,
I.
,
Kim
,
B.
,
Park
,
S.P.
,
Joe
,
E.-H.
et al (
2016
)
Interplay between leucine-Rich repeat kinase 2 (LRRK2) and p62/SQSTM-1 in selective autophagy
.
PLoS One
11
,
e0163029
102
Schapansky
,
J.
,
Khasnavis
,
S.
,
DeAndrade
,
M.P.
,
Nardozzi
,
J.D.
,
Falkson
,
S.R.
,
Boyd
,
J.D.
et al (
2018
)
Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons
.
Neurobiol. Dis.
111
,
26
35
103
Wallings
,
R.
,
Connor-Robson
,
N.
and
Wade-Martins
,
R.
(
2019
)
LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function
.
Hum. Mol. Genet.
28
,
2696
2710
104
Korecka
,
J.A.
,
Thomas
,
R.
,
Christensen
,
D.P.
,
Hinrich
,
A.J.
,
Ferrari
,
E.J.
,
Levy
,
S.A.
et al (
2019
)
Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson's disease patient fibroblasts
.
Hum. Mol. Genet.
105
Ramonet
,
D.
,
Daher
,
J.P.L.
,
Lin
,
B.M.
,
Stafa
,
K.
,
Kim
,
J.
,
Banerjee
,
R.
et al (
2011
)
Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2
.
PLoS ONE
6
,
e18568
106
Hinkle
,
K.M.
,
Yue
,
M.
,
Behrouz
,
B.
,
Dächsel
,
J.C.
,
Lincoln
,
S.J.
,
Bowles
,
E.E.
et al (
2012
)
LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors
.
Mol. Neurodegener.
7
,
25
107
Tong
,
Y.
,
Giaime
,
E.
,
Yamaguchi
,
H.
,
Ichimura
,
T.
,
Liu
,
Y.
,
Si
,
H.
et al (
2012
)
Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway
.
Mol. Neurodegener.
7
,
2
108
Baptista
,
M.A.S.
,
Dave
,
K.D.
,
Frasier
,
M.A.
,
Sherer
,
T.B.
,
Greeley
,
M.
,
Beck
,
M.J.
et al (
2013
)
Loss of leucine-Rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs
.
PLoS ONE
8
,
e80705
109
Tsika
,
E.
,
Kannan
,
M.
,
Foo
,
C.S.-Y.
,
Dikeman
,
D.
,
Glauser
,
L.
,
Gellhaar
,
S.
et al (
2014
)
Conditional expression of Parkinson's disease-related R1441C LRRK2 in midbrain dopaminergic neurons of mice causes nuclear abnormalities without neurodegeneration
.
Neurobiol. Dis.
71
,
345
358
110
Tsika
,
E.
,
Nguyen
,
A.P.T.
,
Dusonchet
,
J.
,
Colin
,
P.
,
Schneider
,
B.L.
and
Moore
,
D.J.
(
2015
)
Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of Parkinson's disease
.
Neurobiol. Dis.
77
,
49
61
111
Yue
,
M.
,
Hinkle
,
K.M.
,
Davies
,
P.
,
Trushina
,
E.
,
Fiesel
,
F.C.
,
Christenson
,
T.A.
et al (
2015
)
Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice
.
Neurobiol. Dis.
78
,
172
195
112
Fuji
,
R.N.
,
Flagella
,
M.
,
Baca
,
M.
,
S. Baptista
,
M.A.
,
Brodbeck
,
J.
,
Chan
,
B.K.
et al (
2015
)
Effect of selective LRRK2 kinase inhibition on nonhuman primate lung
.
Sci. Transl. Med.
7
,
273ra15
113
Mamais
,
A.
,
Manzoni
,
C.
,
Nazish
,
I.
,
Arber
,
C.
,
Sonustun
,
B.
,
Wray
,
S.
et al (
2018
)
Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson's disease brains with Lewy body pathology
.
Brain Res.
1701
,
75
84
114
Trost
,
M.
,
English
,
L.
,
Lemieux
,
S.
,
Courcelles
,
M.
,
Desjardins
,
M.
and
Thibault
,
P.
(
2009
)
The phagosomal proteome in interferon-gamma-activated macrophages
.
Immunity
30
,
143
154
115
Pauwels
,
A.-M.
,
Härtlova
,
A.
,
Peltier
,
J.
,
Driege
,
Y.
,
Baudelet
,
G.
,
Brodin
,
P.
et al (
2019
)
Spatiotemporal changes of the phagosomal proteome in dendritic cells in response to LPS stimulation
.
Mol. Cell. Proteom.
18
,
909
922
116
Nguyen
,
A.P.
and
Moore
,
D.J.
(
2017
)
Understanding the GTPase activity of LRRK2: Regulation, function, and neurotoxicity
.
Adv. Neurobiol.
14
,
71
88
117
Funayama
,
M.
,
Li
,
Y.
,
Tomiyama
,
H.
,
Yoshino
,
H.
,
Imamichi
,
Y.
,
Yamamoto
,
M.
et al (
2007
)
Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population
.
Neuroreport
18
,
273
275
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