Leucine-rich repeat kinase: Biological Overview | References
Gene name - Leucine-rich repeat kinase
Synonyms - LRRK2
Cytological map position - 92F4-92F4
Function - signaling
Keywords - synaptic morphogenesis, neuromuscular junction, regulation of microtubule-binding protein Futsch
Symbol - Lrrk
FlyBase ID: FBgn0038816
Genetic map position - 3R:16,461,910..16,469,856 [+]
Classification - protein serine/threonine kinase, GTPase
Cellular location - cytoplasmic
|Recent literature||Lin, C. H., Li, H., Lee, Y. N., Cheng, Y. J., Wu, R. M. and Chien, C. T. (2015). Lrrk regulates the dynamic profile of dendritic Golgi outposts through the golgin Lava lamp. J Cell Biol 210: 471-483. PubMed ID: 26216903
Constructing the dendritic arbor of neurons requires dynamic movements of Golgi outposts (GOPs), the prominent component in the dendritic secretory pathway. GOPs move toward dendritic ends (anterograde) or cell bodies (retrograde), whereas most of them remain stationary. This study shows that Leucine-rich repeat kinase (Lrrk), the Drosophila melanogaster homologue of Parkinson's disease-associated Lrrk2, regulates GOP dynamics in dendrites. Lrrk localized at stationary GOPs in dendrites and suppressed GOP movement. In Lrrk loss-of-function mutants, anterograde movement of GOPs was enhanced, whereas Lrrk overexpression increased the pool size of stationary GOPs. Lrrk interacts with the golgin Lava lamp and inhibits the interaction between Lva and dynein heavy chain, thus disrupting the recruitment of dynein to Golgi membranes. Whereas overexpression of kinase-dead Lrrk causes dominant-negative effects on GOP dynamics, overexpression of the human LRRK2 mutant G2019S with augmented kinase activity promotes retrograde movement. This study reveals a pathogenic pathway for LRRK2 mutations causing dendrite degeneration.
|Ruan, W., Srinivasan, A., Lin, S., Kara, K. I. and Barker, P. A. (2016). Eiger-induced cell death relies on Rac1-dependent endocytosis. Cell Death Dis 7: e2181. PubMed ID: 27054336
Signaling via tumor necrosis factor receptor (TNFR) superfamily members regulates cellular life and death decisions. A subset of mammalian TNFR proteins, most notably the p75 neurotrophin receptor (p75NTR), induces cell death through a pathway that requires activation of c-Jun N-terminal kinases (JNKs). However the receptor-proximal signaling events that mediate this remain unclear. Drosophila express a single tumor necrosis factor (TNF) ligand termed Eiger (Egr) that activates JNK-dependent cell death. This model was exploited to identify phylogenetically conserved signaling events that allow Egr to induce JNK activation and cell death in vivo. This study reports that Rac1, a small GTPase, is specifically required in Egr-mediated cell death. rac1 loss of function blocks Egr-induced cell death, whereas Rac1 overexpression enhances Egr-induced killing. Vav was identified as a GEF for Rac1 in this pathway, and dLRRK functions were identified as a negative regulator of Rac1 that normally acts to constrain Egr-induced death. Thus dLRRK loss of function increases Egr-induced cell death in the fly. Rac1-dependent entry of Egr into early endosomes was shown to be a crucial prerequisite for JNK activation and for cell death and show that this entry requires the activity of Rab21 and Rab7. These findings reveal novel regulatory mechanisms that allow Rac1 to contribute to Egr-induced JNK activation and cell death.
|De Rose, F., Corda, V., Solari, P., Sacchetti, P., Belcari, A., Poddighe, S., Kasture, S., Solla, P., Marrosu, F. and Liscia, A. (2016). Drosophila mutant model of Parkinson's disease revealed an unexpected olfactory performance: Morphofunctional evidences. Parkinsons Dis 2016: 3508073. PubMed ID: 27648340
Parkinson's disease (PD) is one of the most common neurodegenerative diseases characterized by the clinical triad: tremor, akinesia, and rigidity. Several studies have suggested that PD patients show disturbances in olfaction as one of the earliest, nonspecific nonmotor symptoms of disease onset. This study sought to use the fruit fly Drosophila melanogaster as a model organism to explore olfactory function in LRRK loss-of-function mutants, which was previously demonstrated to be a useful model for PD. Surprisingly, the results showed that the LRRK mutant, compared to the wild flies, presents a dramatic increase in the amplitude of the electroantennogram responses and this is coupled with a higher number of olfactory sensilla. In spite of the above reported results, the behavioural response to olfactory stimuli in mutant flies is impaired compared to that obtained in wild type flies. Thus, behaviour modifications and morphofunctional changes in the olfaction of LRRK loss-of-function mutants might be used as an index to explore the progression of parkinsonism in this specific model, also with the aim of studying and developing new treatments.
|Quintero-Espinosa, D., Jimenez-Del-Rio, M. and Velez-Pardo, C. (2016). Knockdown transgenic Lrrk Drosophila resists paraquat-induced locomotor impairment and neurodegeneration: A therapeutic strategy for Parkinson's disease. Brain Res. PubMed ID: 28041945
Leucine-rich repeat kinase 2 (LRRK2) has been linked to familial and sporadic Parkinson's disease. However, it is still unresolved whether LRRK2 in dopaminergic (DAergic) neurons may or may not aggravate the phenotype. This study demonstrate that knocking down (KD) the Lrrk gene by RNAi in DAergic neurons untreated or treated with paraquat (PQ) neither affected the number of DAergic clusters, tyrosine hydroxylase (TH) protein levels, lifespan nor locomotor activity when compared to control (i.e. TH/+) flies. KD transgenic Lrrk flies dramatically increased locomotor activity in presence of TH enzyme inhibitor α-methyl-para-tyrosine (aMT), whereas no effect on lifespan was observed in both fly lines. Most importantly, KD Lrrk flies had reduced lipid peroxidation (LPO) index alone or in presence of PQ and the antioxidant minocycline (MC, 0.5 mM). Taken together, these findings suggest that Lrrk appears unessential for the viability of DAergic neurons in D. melanogaster. Moreover, Lrrk might negatively regulate homeostatic levels of dopamine, thereby dramatically increasing locomotor activity, extending lifespan, and reducing oxidative stress (OS). These data also indicate that reduced expression of Lrrk in the DAergic neurons of transgenic TH>Lrrk-RNAi/+ flies conferred PQ resistance and absence of neurodegeneration. The findings support the notion that reduced/suppressed LRRK2 expression might delay or prevent motor symptoms and/or frank Parkinsonism in individuals at risk to suffer autosomal dominant Parkinsonism (AD-P) by blocking OS-induced neurodegenerative processes in the DAergic neurons.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are linked to familial as well as sporadic forms of Parkinson's disease (PD), a neurodegenerative disease characterized by dysfunction and degeneration of dopaminergic and other types of neurons. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. This study shows that LRRK2 controls synaptic morphogenesis at the Drosophila neuromuscular junction. Loss of Drosophila LRRK2 results in synaptic overgrowth, whereas overexpression of Drosophila LRRK or human LRRK2 has opposite effects. Alteration of LRRK2 activity also affects neurotransmission. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the presynaptic and postsynaptic compartments. At the postsynapse, LRRK2 interacts with the previously characterized substrate 4E-BP (Imai, 2008), an inhibitor of protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule (MT)-binding protein Futsch. These results implicate synaptic dysfunction caused by deregulated protein synthesis and aberrant MT dynamics in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating PD (Lee, 2010).
Parkinson's disease (PD) is one of the most common neurodegenerative diseases and is characterized by locomotor abnormalities as a result of the dysfunction and eventual loss of dopaminergic (DA) neurons. Most PD cases are sporadic with no known cause. Recent advances in PD genetics have led to the identification of familial PD (FPD) genes. It is anticipated that understanding the disease mechanisms of the FPD cases will provide insights into PD pathogenesis in general. Despite intensive studies of the FPD gene products at the biochemical and cell biological levels, understanding of their physiological function and the molecular and cellular pathways underlying disease pathogenesis is still fragmentary. Of all FPD genes, leucine-rich repeat kinase 2 (LRRK2) is the most frequently mutated. LRRK2 encodes a large serine/threonine kinase with multiple other domains (Paisan-Ruíz, 2004; Zimprich, 2004). Some pathogenic mutations in LRRK2, such as the I2020T and G2019S substitutions in the kinase domain and R1441C substitution in the ROC domain, appear to augment kinase activity (West, 2005; Gloeckner, 2006). In Drosophila and mouse models, pathogenic human (hLRRK2) or Drosophila (dLRRK) LRRK2 induce parkinsonian phenotypes in an age-dependent manner (Imai, 2008; Liu, 2008; Li, 2009). A number of LRRK2-interacting proteins and substrates have been identified through in vitro studies (Jaleel, 2007; Imai, 2008; Shin, 2008; Gillardon, 2009a; Gillardon, 2009b), which implicate diverse biological functions for LRRK2 in translational control, vesicular trafficking, and cytoskeletal regulation. The physiological relevance of these interacting proteins and substrates remain to be established (Lee, 2010).
Actin and microtubule (MT) cytoskeleton dynamics play a crucial role in the formation of the nervous system, regulating such fundamental processes as axonal guidance and synaptogenesis. Dynamic modulation of synaptic structure and function is fundamental to neural network formation during development and is the molecular basis of learning and memory. Synaptic dysfunction is tightly linked to the pathogenesis of major neurodegenerative diseases such as Alzheimer's disease, and its role in PD is beginning to be appreciated (Calabresi, 2007). In Drosophila, the MT-associated protein 1B (MAP1B) homolog Futsch is required for axonal and dendritic growth during embryogenesis and for synaptic morphogenesis during larval neuromuscular junction (NMJ) development. This study shows that dLRRK phosphorylates and negatively regulates Futsch function at the presynapse. The previously characterized dLRRK substrate 4E-BP functionally interacts with LRRK2 at the postsynapse. These results implicate defects in presynaptic MT cytoskeleton dynamics and postsynaptic protein synthesis in LRRK2 pathogenesis (Lee, 2010).
Genetic mutations in LRRK2 are frequently found in familial and sporadic PD cases. Understanding the physiological function of LRRK2 will therefore offer insights into PD pathogenesis in general. This study reveals a new physiological function of LRRK2 and offers molecular mechanisms underlying such function. The key findings from this study are that LRRK2 plays an important role in regulating synaptic morphogenesis and that it does so through distinct substrate proteins at the presynaptic and postsynaptic compartments. The results also show that the precise level of LRRK2 activity is important for synaptic morphogenesis and neurotransmission, but the regulation of these two synaptic processes likely involve different mechanisms and players. Given the similarity of Drosophila NMJ synapse to mammalian excitatory glutamatergic synapses, it is possible that the findings reported here are relevant to mammalian systems (Lee, 2010).
Synaptic loss is a major neurobiological substrate of cognitive dysfunction in a number of neurological diseases. Extensive studies in patients and animal models have documented that synaptic failure is one of the earliest events in the pathogenesis of Alzheimer's disease. Interestingly, neurotransmission defects have been repeatedly observed in rodent FPD models, including the LRRK2 model (Tong, 2009), although no obvious signs of neurodegeneration accompany the electrophysiological defects. These results suggest that synaptic dysfunction is a primary effect of FPD gene mutations and that synaptic failure is intimately involved in PD pathogenesis. The molecular mechanisms underlying these synaptic transmission defects, however, remain elusive. This study of the LOF and GOF models of LRRK2 in Drosophila provides mechanistic insights into the possible cause of synaptic dysfunction in LRRK2-associated PD. It was found that LRRK2 regulates synaptic morphogenesis at the presynaptic and postsynaptic compartments through distinct substrates (Lee, 2010).
In the presynaptic side, LRRK2 forms a complex with tubulin and the MT-binding protein Futsch. Furthermore, LRRK2 phosphorylates Futsch and negatively regulates the presynaptic function of Futsch in controlling MT dynamics. MT cytoskeleton is critical for the generation and maintenance of neuronal axons and dendrites, transport of synaptic vesicles and organelles along the processes, and the initiation and maintenance of synaptic transmission. Disrupted MT dynamics in neuronal synapses has been implicated as an underlying cause for several neurological diseases, including hereditary spastic paraplegia and fragile X syndrome. LRRK2-associated PD may share this feature with the aforementioned diseases. Disrupted MT dynamics could be responsible for the presynaptic effects observed in LRRK2 LOF and GOF mutants, such as aberrant mitochondria distribution. The synaptic vesicle transport phenotypes seen in Caenorhabditis elegans LRK-1 mutant could also be attributable to altered MT dynamics (Sakaguchi-Nakashima, 2007). These could all contribute to synaptic dysfunction. Futsch/MAP1B proteins are large multidomain proteins that are phosphorylated by multiple kinases, including Sgg/GSK-3β, PAR-1/MARK, and Cdk5, which also phosphorylate tau and are implicated in tau pathology. Tau-related pathology has been observed in LRRK2 transgenic animals (Li, 2009). It would be interesting to test for possible interplay between LRRK2 and these other kinases in regulating MT-binding proteins and MT dynamics. In mammalian hippocampal neurons, overexpression of pathogenic hLRRK2 led to reduced neurite length and branching, whereas deficiency of LRRK2 had opposite effects (MacLeod, 2006). Whether MT dynamics regulated by Futsch/MAP1B is contributing to this LRRK2 effect in mammals will await additional investigation (Lee, 2010).
This study also showed that LRRK2 interacts with 4E-BP at the postsynapse. 4E-BP acts as a negative regulator of the translational initiation factor eIF4E through direct binding and sequestration. Phosphorylation of 4E-BP by LRRK2 weakens 4E-BP binding to eIF4E (Imai, 2008), therefore releasing the inhibitory effect of 4E-BP on eIF4E. Previous studies have demonstrated an important postsynaptic role for eIF4E-mediated protein synthesis in activity-dependent synaptic growth at the Drosophila NMJ (Sigrist, 2000). Genetic interaction studies demonstrate a functional role for 4E-BP in mediating the synaptic effects of LRRK2. However, the exact roles of 4E-BP and LRRK2 in this process appear complex. For example, (1) despite the prominent effects of 4E-BP overexpression on NMJ development, its loss of function has no obvious effect. One would expect a gain of eIF4E function in the absence of 4E-BP and therefore a synaptic-overgrowth phenotype. (2) 4E-BP activity is predicted to be high in dLRRK mutant and low in LRRK2 overexpression condition, but this study observed synapse phenotypes opposite of what is predicted based on the presumed roles of eIF4E and 4E-BP on Drosophila NMJ morphogenesis. One possible explanation of these seemingly disparate results is that phospho-4E-BP, the product of LRRK2-mediated phosphorylation of 4E-BP, instead of being inactive and inert, may actually perform some new synaptic function at the NMJ. In this scenario, loss of 4E-BP function in d4E-BP mutant would not show the same phenotype as LRRK2 overexpression, which produces more phospho-4E-BP. Recent studies in Drosophila dopaminergic neurons suggest a functional role for phospho-4E-BP in vivo (Gehrke, 2010). Alternately, effectors other than 4E-BP may also mediate the effects of LRRK2 on NMJ development and neurotransmission. Although 4E-BP overexpression might have masked the effects of these other effectors, in dLRRK mutant background, the functional roles of these other effectors might manifest themselves. A similar situation was observed in pumillo mutant, in which a synapse-loss phenotype was observed despite the upregulation of eIF4E activity in this mutant attributable to the derepression of translational inhibition of eIF4E, which would have resulted in a predicted synapse-overgrowth phenotype. Involvement of other effectors in mediating the effects of LRRK2 on NMJ development and neurotransmission, and possibly different effectors for NMJ development versus neurotransmission, could also explain the complex electrophysiological phenotypes of dLRRK mutant and LRRK2 overexpression animals, as well as the uncoupling of the effects on synaptic differentiation and neurotransmission by the various genetic manipulations. Future studies will test these possibilities as well as the relevance of the NMJ studies to dopaminergic neuron synapses (Lee, 2010).
In addition to LRRK2, the TOR pathway also regulates 4E-BP function through phosphorylation. This pathway primarily regulates cell and organism growth through diverse outputs, including protein synthesis, cytoskeletal change, autophagy, and cell survival. This study found that treatment of flies with rapamycin, an inhibitor of TOR, has the same effects as 4E-BP overexpression in wild type as well as LRRK2 overexpression backgrounds. Although rapamycin has been extensively studied in the context of autophagy induction and neurodegeneration models, its effect on Drosophila NMJ development is unlikely attributable to autophagy, because the current results show that presynaptic or postsynaptic induction of autophagy through Atg1 overexpression had no obvious effect on synapse number. The similar effects of rapamycin and 4E-BP overexpression on NMJ development support that rapamycin acts via the 4E-BP translational control pathway to impact NMJ development. A recent report showed that either 4E-BP overexpression or 4E-BP activation by rapamycin could suppress the muscle and dopaminergic neurodegeneration phenotypes seen in Drosophila Pink1 and Parkin models of PD (Tain, 2009). These results suggest that deregulation of protein synthesis could be generally involved in PD pathogenesis and that rapamycin or its analogs could be developed into effective PD therapeutics (Lee, 2010).
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of dominant-inherited Parkinson's disease (PD), and yet the physiological functions of LRRK2 are not fully understood. Various components of the clathrin machinery have been recently found mutated in familial forms of PD. This study provides molecular insight into the association of LRRK2 with the clathrin machinery. Through its GTPase domain, LRRK2 binds directly to clathrin-light chains (CLCs). Using genome-edited HA-LRRK2 cells, LRRK2 was localized to endosomes on the degradative pathway, where it partially co-localizes with CLCs. Knockdown of CLCs and/or LRRK2 enhances the activation of the small GTPase Rac1, leading to alterations in cell morphology, including the disruption of neuronal dendritic spines. In Drosophila, a minimal rough eye phenotype caused by overexpression of Rac1, is dramatically enhanced by loss of function of CLC and LRRK2 homologues, confirming the importance of this pathway in vivo. These data identify a new pathway in which CLCs function with LRRK2 to control Rac1 activation on endosomes, providing a new link between the clathrin machinery, the cytoskeleton and PD (Schreij, 2014).
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent molecular lesions so far found in Parkinson's disease (PD), an age-dependent neurodegenerative disorder affecting dopaminergic (DA) neuron. The molecular mechanisms by which mutations in LRRK2 cause DA degeneration in PD are not understood. This study shows that both human LRRK2 and the Drosophila orthologue of LRRK2 phosphorylate eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP), a negative regulator of eIF4E-mediated protein translation and a key mediator of various stress responses. Although modulation of the eIF4E/4E-BP pathway by LRRK2 stimulates eIF4E-mediated protein translation both in vivo and in vitro, it attenuates resistance to oxidative stress and survival of DA neuron in Drosophila. These results suggest that chronic inactivation of 4E-BP by LRRK2 with pathogenic mutations deregulates protein translation, eventually resulting in age-dependent loss of DA neurons (Imai, 2008).
This study used Drosophila as a model system to understand the normal physiological function of LRRK2 and how its dysfunction leads to DA neurodegeneration. Genetic and biochemical evidence is provided that dLRRK modulates the maintenance of DA neuron by regulating protein synthesis. LRRK2 primes phosphorylation of 4E-BP, and this event has an important function in mediating the pathogenic effects of mutant dLRRK. These results link deregulation of the eIF4E/4E-BP pathway of protein translation with DA degeneration in PD (Imai, 2008).
eIF4E is a key component of the eIF4F complex that initiates cap-dependent protein synthesis. It has long been recognized that a key mechanism regulating eIF4E function is through phosphorylation-induced release of 4E-BP from eIF4E. A number of candidate kinases, including mTOR, have been implicated on the basis of in vitro or cell culture studies, but the physiological kinases remain to be identified. This study shows that LRRK2 is one of the physiological kinases for 4E-BP. LRRK2 exerts an effect on 4E-BP primarily at the T37/T46 sites. Phosphorylation at T37/T46 by LRRK2 likely facilitates subsequent phosphorylation at T70 and S65 in vivo by other kinase or LRRK2 itself. 4E-BP phosphorylation by LRRK2, therefore, could serve as an initiating event in an ordered, multisite phosphorylation process to generate hyperphosphorylated 4E-BP, similar to the phosphorylation of the Alzheimer's disease-associated tau. These results show that LRRK2 is not the only kinase that phosphorylates 4E-BP T37/T46 sites. Similarly, 4E-BP is unlikely the only substrate of LRRK2. A recent study showed that human LRRK2 phosphorylates moesin (Jaleel, 2007), the physiological relevance of which remains to be determined (Imai, 2008).
The role of 4E-BP in regulating eIF4E function has been well established in vitro. Recent studies in Drosophila, however, have revealed the complexity of the in vivo function of 4E-BP. Loss of the only d4E-BP gene does not affect cell size or animal viability (Bernal, 2000), suggesting that it is dispensable for cell growth or survival under normal conditions. However, d4E-BP mutant flies are defective in responses to various stress stimuli. d4E-BP has also been proposed to exert an effect as a metabolic brake for fat metabolism under stress condition. Whether this role of 4E-BP is relevant to dLRRK function in stress resistance and DA neuron maintenance remains to be tested. eIF4E, the target of 4E-BP, functions primarily in regulating general protein translation in vitro. It has been suggested that overactivation of eIF4E is linked to the aging process and lifespan regulation. This study observed that overexpression of eIF4E as well as dLRRK leads to an aging-related phenotype in DA neurons, which strongly suggested that chronic attenuation of 4E-BP activity promotes oxidative stress and consequent aging in DA neurons. This is consistent with the finding of similar patterns of gene expression under oxidative stress and aging conditions, and the fact that PD caused by LRRK2 mutations is of late onset, with aging being a major risk factor (Imai, 2008).
This study analysed effects of removing dLRRK activity using a transposon insertion allele (dLRRK−), a chromosomal deletion allele (dLRRK Df) and gene knockdown (dLRRK RNAi). dLRRK(−/−), dLRRK (Df/−) and dLRRK RNAi flies are all resistant to oxidative stress treatments and show reduced endogenous ROS damages. In the paraquat treatment assay, dLRRK (Df/−) appeared more resistant than dLRRK(−/−). It is possible that dLRRK(−/−), which contains a transposon insertion in the COR domain of dLRRK, is not a null allele, although it has not been possible to detect a truncated protein product using an antibody against the N-terminus of the protein. Alternatively, the chromosomal deletion in dLRRK (Df) may include other gene(s) relevant to stress sensitivity. One candidate is the gene for PI3K Dp110 subunit. A recent study reported that dLRRK(−/−) animals are slightly sensitive to hydrogen peroxide but are comparable to control animals in response to paraquat (Wang, 2008). It is possible that the different genetic backgrounds and the nutrient conditions may account for the divergent results. In the current studies, the mutant chromosome was backcrossed to w− WT background for six generations in an effort to eliminate potential background mutations. A consistent finding from this study and two other studies of dLRRK(−/−) animals is that dLRRK is dispensable for the maintenance of DA neurons (Lee, 2007; Wang, 2008), although in one study it was reported that dLRRK(−/−) animals show reduced TH immunoreactivity and shrunken morphology of DA neurons (Lee, 2007). In contrast, overexpression of hLRRK2 containing a pathogenic G2019S mutation (Liu, 2008), or overexpression of mutant dLRRK as reported in this study, caused DA neuron degeneration, supporting the fact that the pathogenic mutations cause disease by a GOF mechanism (Imai, 2008).
The pathogenesis caused by mutations in LRRK2 could be partially explained by their higher kinase activity. Indeed, some pathogenic mutants of both hLRRK2 and dLRRK show elevated kinase activity towards 4E-BP. However, other mutants (e.g., hLRRK2 Y1699C and dLRRK Y1383C) did not show elevated kinase activity in vivo. Therefore, these pathogenic hLRRK2 mutations might confer cellular toxicity through mechanisms other than protein translation. For example, some hLRRK2 mutants are prone to aggregation in cultured cells (Smith, 2005; Greggio, 2006). Consistently, dLRRK Y1383C mutant appeared as more prominent vesicular aggregates in fly DA neurons. Nevertheless, the facts that overexpression of eIF4E is sufficient to confer hypersensitivity to oxidative stress and DA neuron loss and that co-expression of 4E-BP suppresses the dopaminergic toxicity caused by more than one pathogenic dLRRK mutants provide compelling evidence that the eIF4E-4E-BP axis has an important function in mediating the pathogenic effects of overactivated LRRK2. The more downstream events that lead to DA neurotoxicity remain to be elucidated. So far, no clear evidence has been found of altered autophagy, caspase activation or DNA fragmentation (Imai, 2008).
There are several possibilities of how elevated protein translation could contribute to PD pathogenesis. First, given that protein synthesis is a highly energy-demanding process, stimulation of protein translation by LRRK2 could perturb cellular energy and redox homoeostasis. This could be especially detrimental in aged cells or stressed post-mitotic cells such as DA neurons. Second, increased protein synthesis could lead to the accumulation of misfolded or aberrant proteins, overwhelming the already compromised ubiquitin proteasome and molecular chaperone systems in aged or stressed cells. Third, altered LRRK2 kinase activity may affect synapse structure and function, which is known to involve local protein synthesis. Deregulation of this process could lead to synaptic dysfunction and eventual neurodegeneration (Imai, 2008).
Parkinson's disease (PD) is the most prevalent incurable neurodegenerative movement disorder. Mutations in LRRK2 are associated with both autosomal dominant familial and sporadic forms of PD. LRRK2 encodes a large putative serine/threonine kinase with GTPase activity. Increased LRRK2 kinase activity plays a critical role in pathogenic LRRK2 mutant-induced neurodegeneration in vitro. Little is known about the physiological function of LRRK2. A Drosophila line has been identified with a P-element insertion in an ortholog gene of human LRRK2 (dLRRK). The insertion results in a truncated Drosophila LRRK variant with N-terminal 1290 amino acids but lacking C-terminal kinase domain. The homozygous mutant fly develops normally with normal life span as well as unchanged number and pattern of dopaminergic neurons. However, dLRRK mutant flies were selectively sensitive to hydrogen peroxide induced stress but not to paraquat, rotenone and beta-mercaptoethanol induced stresses. These results indicate that inactivation of dLRRK kinase activity is not essential for fly development and suggest that inhibition of LRRK activity may serve as a potential treatment of PD. However, dLRRK kinase activity likely plays a role in protecting against oxidative stress (Wang, 2008; full text of article).
Mutations in the leucine-rich repeat kinase (LRRK2) gene cause late-onset autosomal dominant Parkinson's disease (PD) with pleiomorphic pathology. Previously studies have found that expression of mutant LRRK2 causes neuronal degeneration in cell culture. This study used the GAL4/UAS system to generate transgenic Drosophila expressing either wild-type human LRRK2 or LRRK2-G2019S, the most common mutation associated with PD. Expression of either wild-type human LRRK2 or LRRK2-G2019S in the photoreceptor cells caused retinal degeneration. Expression of LRRK2 or LRRK2-G2019S in neurons produced adult-onset selective loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Expression of mutant G2019S-LRRK2 caused a more severe parkinsonism-like phenotype than expression of equivalent levels of wild-type LRRK2. Treatment with l-DOPA improved mutant LRRK2-induced locomotor impairment but did not prevent the loss of tyrosine hydroxylase-positive neurons. This is the first in vivo 'gain-of-function' model which recapitulates several key features of LRRK2-linked human parkinsonism. These flies may provide a useful model for studying LRRK2-linked pathogenesis and for future therapeutic screens for PD intervention (Liu, 2008; full text of article).
Search PubMed for articles about Drosophila Lrrk2
Calabresi, P., et al. (2007). Neuronal networks and synaptic plasticity in Parkinson's disease: beyond motor deficits. Parkinsonism Relat. Disord. 13 [Suppl 3]: S259-S262. PubMed ID: 18267247
Gehrke, S., Imai, Y., Sokol, N. and Lu, B. (2010). Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466: 637-641. PubMed ID: 20671708
Gillardon, F. (2009a). Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability: a point of convergence in parkinsonian neurodegeneration? J. Neurochem. 110: 1514-1522. PubMed ID: 19545277
Gillardon, F. (2009b). Interaction of elongation factor 1-alpha with leucine-rich repeat kinase 2 impairs kinase activity and microtubule bundling in vitro. Neuroscience 163: 533-539. PubMed ID: 19559761
Gloeckner, C. J., et al. (2006). The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. 15: 223-232. PubMed ID: 16321986
Greggio, E., et al. (2006). Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. 23: 329-341. PubMed ID: 16750377
Imai, Y., et al. (2008). Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J. 27: 2432-2443. PubMed ID: 18701920
Jaleel, M., et al. (2007). LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem. J. 405: 307-317. PubMed ID: 17447891
Lee, S., Liu, H. P., Lin, W. Y., Guo, H. and Lu, B. (2010). LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. J. Neurosci. 30(50): 16959-69. PubMed ID: 21159966
Li, Y., et al. (2009). Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat. Neurosci. 12: 826-828. PubMed ID: 19503083
Liu. Z., et al. (2008). A Drosophila model for LRRK2-linked parkinsonism. Proc. Natl. Acad. Sci. 105: 2693-2698. PubMed ID: 18258746
MacLeod, D., et al. (2006). The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52: 587-593. PubMed ID: 17114044
Paisan-Ruíz, C., et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44: 595-600. PubMed ID: 15541308
Sakaguchi-Nakashima, A., et al. (2007). LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr. Biol. 17: 592-598. PubMed ID: 17346966
Schreij, A. M., Chaineau, M., Ruan, W., Lin, S., Barker, P. A., Fon, E. A. and McPherson, P. S. (2014). LRRK2 localizes to endosomes and interacts with clathrin-light chains to limit Rac1 activation. EMBO Rep 16(1):79-86. PubMed ID: 25427558
Shin, N., et al. (2008). LRRK2 regulates synaptic vesicle endocytosis. Exp. Cell Res. 314: 2055-2065. PubMed ID: 18445495
Sigrist, S. J., et al. (2000). Postsynaptic translation affects the efficacy and morphology of neuromuscular junctions. Nature 405: 1062-1065. PubMed ID: 10890448
Smith, W. W., et al. (2005). Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl. Acad. Sci. 102: 18676-18681. PubMed ID: 16352719
Tain, L. S., et al. (2009). Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat. Neurosci. 12: 1129-1135. PubMed ID: 19684592
Tong, Y. and Shen, J. (2009). alpha-synuclein and LRRK2: partners in crime. Neuron 64(6): 771-3. PubMed ID: 20064381
Wang, D., et al. (2008). Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons. Mol. Neurodegener. 3: 3. PubMed ID: 18257932
West, A. B., et al. (2005). Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. 102: 16842-16847. PubMed ID: 16269541
Zimprich A, et al. (2004). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44: 601-607. PubMed ID: 15541309
date revised: 20 March 2015
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