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LRRK2: Function and Dysfunction The importance of Wnt signalling for neurodegeneration in Parkinson’s disease Daniel C. Berwick and Kirsten Harvey1 Department of Pharmacology, UCL School of Pharmacy, University College London, 29–39 Brunswick Square, London WC1N 1AX, U.K. Abstract PD (Parkinson’s disease) is a devastating progressive motor disorder with no available cure. Over the last two decades, an increasing number of genetic defects have been found that cause familial and idiopathic forms of PD. In parallel, the importance of Wnt signalling pathways for the healthy functioning of the adult brain and the dysregulation of these pathways in neurodegenerative disease has become apparent. Cell biological functions disrupted in PD are partially controlled by Wnt signalling pathways and proteins encoded by PARK genes have been shown to modify Wnt signalling. This suggests the prospect of targeting Wnt signalling pathways to modify PD progression. Introduction PD (Parkinson’s disease) is the second most prevalent neurodegenerative disease worldwide. Individuals with PD present with typical motor symptoms, such as resting tremor and bradykinesia, caused by the progressive loss of ventral midbrain dopaminergic (dopamine-producing) neurons of the substantia nigra pars compacta [1]. The classical hallmark found in PD post-mortem brains are Lewy bodies, protein depositions enriched in α-synuclein. The identification of mutations in PARK genes as a cause of familial PD over the last 15 years raises the hope of finding a common cellular defect underlying PD [1]. However, despite extensive research, the initial cellular mechanisms triggering PD remain largely uncharacterized. In the present paper, we provide evidence that indicates a critical importance of Wnt signalling pathways for the normal function and survival of midbrain dopaminergic neurons. We further suggest deregulated Wnt signalling as a potential cause of PD. Currently, PD symptoms can be improved with dopamine-replacement therapy, but disease-modifying treatments that slow or reverse disease progression are not available. Therefore the characterization of signalling pathways deregulated in PD is important for the identification of new drug targets. Wnt signalling pathways Wnt (Wingless/Int) signalling pathways have been most widely studied in the fields of embryogenesis and cancer Key words: genetics of Parkinson’s disease, leucine-rich repeat kinase 2 (LRRK2), neurodegeneration, Parkinson’s disease, treatment, Wnt signalling. Abbreviations used: AD, Alzheimer’s disease; AP1, activator protein 1; ApoE4, apolipoprotein E4; CaMK, Ca2 + /calmodulin-dependent kinase; CREB, cAMP-response-element-binding protein; DAG, diacylglycerol; Dkk1, Dickkopf-1; DVL, Dishevelled; Fz, Frizzled; GSK3β, glycogen synthase kinase 3β; GWAS, genome-wide association study; JNK, c-Jun N-terminal kinase; LEF, lymphoid enhancer-binding factor; LRP, low-density-lipoprotein-related protein; LRRK2, leucine-rich repeat kinase 2; MAP3K7, mitogen-activated protein kinase kinase kinase 7; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor κB; PCP, planar cell polarity; PD, Parkinson’s disease; PKC, protein kinase C; ROC, Ras of complex proteins; TCF, T-cell transcription factor; Wnt, Wingless/Int. 1 To whom correspondence should be addressed (email [email protected]). Biochem. Soc. Trans. (2012) 40, 1123–1128; doi:10.1042/BST20120122 biology [2]. Nonetheless, the importance of these pathways for maintaining physiological function in the adult brain is becoming increasingly clear. Wnt signalling cascades fit a textbook idea of signal transduction, linking an extracellular stimulus to altered gene expression via plasma membrane receptors and intracellular signalling mechanisms [2–4]. The binding of secreted Wnt ligands to Fz (Frizzled) receptors and associated co-receptors at the cell membrane leads to hyperphosphorylation of DVL (Dishevelled) proteins and the subsequent downstream activation of one of three Wnt signalling cascades [3,4] known as the canonical Wnt, the noncanonical Wnt/PCP (planar cell polarity) and the Wnt/Ca2 + pathways (Figure 1). The canonical Wnt signalling pathway is the best characterized Wnt pathway. Under basal conditions, βcatenin is phosphorylated by GSK3β (glycogen synthase kinase 3β) as part of a cytoplasmic multiprotein complex known as the β-catenin destruction complex. Phosphorylated β-catenin is ubiquitinated and degraded by the proteasome [2–5]. Wnt ligand binding to Fz receptors and LRP (lowdensity-lipoprotein-related protein) 5/6 co-receptors activates signalling. This signal is transduced by DVL proteins, leading to the inhibition of GSK3β and stabilization of cytoplasmic β-catenin allowing translocation to the nucleus. Classically, nuclear β-catenin binds to and derepresses members of the TCF (T-cell transcription factor)/LEF (lymphoid enhancer-binding factor) family of transcription factors, thus up-regulating Wnt target gene expression. However, it is important to note that a number of other transcription factors have been identified as β-catenin targets [2]. Non-canonical Wnt signalling pathways, including the Wnt/PCP and the Wnt/Ca2 + pathway, are executed independently of β-catenin [3–5]. In the Wnt/PCP pathway, signalling downstream of DVL proteins is mediated by small GTPases, in particular RhoA and Rac1. Outputs of this cascade include cytoskeletal rearrangements and activation of AP1 (activator protein 1)-dependent transcription, in both C The C 2012 Biochemical Society Authors Journal compilation 1123 1124 Biochemical Society Transactions (2012) Volume 40, part 5 Figure 1 Wnt signalling cascades In the canonical Wnt pathway (left), binding of extracellular Wnt ligand to Fz receptors and LRP5/6 co-receptors induces an intracellular cascade transduced via DVL proteins. This signal leads to the inhibition of a subset of cellular GSK3β, contained within so-called BDCs (β-catenin destruction complexes). The central BDC components axin and APC (adenomatous polyposis coli) are depicted. In consequence, the GSK3β-mediated phosphorylation and repression of β-catenin (β-cat) is relieved, leading to the accumulation and nuclear translocation of β-catenin. Within the nucleus, β-catenin binds to TCF/LEF family transcription factors, thereby regulating gene expression. Note that canonical Wnt signalling can also affect the phosphorylation of other GSK3β targets, whereas β-catenin can also modulate transcription driven by other transcription factors. In the non-canonical/PCP pathway (centre), signalling leads to the activation of small GTPases, particularly RhoA and Rac1. Classical outputs of this pathway include cytoskeletal rearrangements and the activation of the JNK pathway, leading to activation of AP1-mediated gene expression. The Wnt/Ca2 + pathway (right) leads to increased levels of two intracellular second messengers: Ca2 + and DAG. Multiple downstream effectors have been reported (see the text); depicted are the activation of PKC and CaMK leading to activation of NF-κB- and CREB-dependent transcription, and also up-regulation of an additional transcription factor, NFAT. MAP1B, microtubule-associated protein 1B; ROCK, Rho-associated kinase; ROR2, receptor tyrosine kinase-like orphan receptor 2. cases via the activation of JNK (c-Jun N-terminal kinase). Activation of the Wnt/Ca2 + pathway results in an increase in intracellular Ca2 + . Increased Ca2 + in turn activates PKC (protein kinase C) and CaMK (Ca2 + /calmodulindependent kinase) II [3–5]. These kinases have known effects on cellular signalling in a context-dependent manner, e.g. phosphorylation of postsynaptic receptors in neurons [6]. A growing number of other Wnt/Ca2 + effector pathways have been described, including the Ca2 + /calcineurin/NFAT [7], Ca2 + /MAP3K7/NLK/TCF/LEF [8,9], Ca2 + /MAP3K7/ NF-κB [10] and DAG/PKC/NF-κB/CREB [11,12] pathways, as well as the actin-polymerization-dependent DVL/RhoA/ROCK pathway [8]; NFAT is nuclear factor of activated T-cells, MAP3K7 is mitogen-activated protein kinase kinase kinase 7, NLK is NEMO [NF-κB (nuclear factor κB) essential modulator]-like kinase, DAG is diacylglycerol, CREB is cAMP-response-element-binding protein, C The C 2012 Biochemical Society Authors Journal compilation and ROCK is Rho-associated kinase. These numerous pathways underline the complexity of Wnt signalling. In humans, 19 Wnt ligands, ten Fz receptors and numerous co-receptors have been described, with the expression of each component under exquisite spatiotemporal control. The simultaneous activation of more than one pathway can elicit agonistic or antagonistic cross-talk, probably depending on expression levels of signalling components [9,13]. This level of complexity inevitably requires precise regulation, but, perhaps more relevantly, also creates more scope for subtle defects to occur. Wnt signalling in the adult brain Wnt pathways are required for the development of the central nervous system [4,14], and growing evidence implicates Wnt cascades as crucial participants in adult neurogenesis [15]. LRRK2: Function and Dysfunction However, recent advances indicate the critical importance of Wnt signalling for the function of mature neurons. Importantly, Wnt pathways play roles on both sides of the synapse. For example, presynaptic vesicle cycling is modulated by the Wnt ligands Wnt7a and Wnt3a in a β-catenindependent, but transcription-independent, pathway [6,16]. Correspondingly, the trafficking of postsynaptic neurotransmitter receptors and their interaction with scaffolding proteins can be regulated by Wnt signals [6,17]. Furthermore, transcription-dependent effects of Wnt ligand have been documented. For example, canonical Wnt signalling has been shown to drive the expression of the Ca2 + channel Cav 3.1 in the adult thalamus, leading to enhanced T-type Ca2 + currents [18]. Finally, and perhaps most intriguingly, electrophysiological stimulation of excitatory synapses is sufficient to activate β-catenin [19]. Thus, in mature neurons, Wnt mechanisms can be both up- and down-stream of synaptic activity, extending from synapses to altered gene expression in the nucleus, and even involve activitydependent feedback mechanisms that underlie learning and memory. In fact, a growing body of data link extracellular Wnt ligands to the modulation of hippocampal synaptic plasticity [6]. Since Wnt signals are clearly involved in the acute regulation of synaptic function, deregulation in the long term is likely to compromise neuronal activity [6]. Wnt signalling in dopaminergic neurons Wnt signalling pathways are also of special relevance to the dopaminergic neurons in the ventral midbrain that play a central role to PD [6,20–22]. For example, a recent study suggested an interaction between dopamine D2 receptors and β-catenin in adult brain. Presumably by sequestering cellular β-catenin, the overexpression of D2 receptors (but not D1 , D3 , D4 or D5 subtypes) inhibited canonical Wnt signalling [23]. However, the vast majority of evidence for the importance of Wnt signalling to dopaminergic neurons comes from developmental biology. Wnt cascades have an established role in dopaminergic neurogenesis in vitro, with roles for Wnt1 and Wnt3a in the specification of committed dopaminergic precursors, and for Wnt5a in their terminal differentiation [24]. These findings have been corroborated in vivo, with impaired dopaminergic development and altered midbrain morphology seen upon disruption of Wnt1 [25], Wnt5a [26] or Lrp6 [27] genes. These experiments are reviewed in detail elsewhere [6], but it is important to note that Wnt1 and LRP6 function specifically within the canonical Wnt pathway, whereas Wnt5a is specific to the non-canonical Wnt/PCP pathway, in this case, probably signalling via the small GTPase Rac1. As such, both canonical and non-canonical cascades appear to be critical for dopaminergic development. The requirements for Wnt1- and LRP6dependent canonical Wnt signalling are almost certainly via β-catenin-dependent gene transcription, especially since βcatenin is itself required for the development of ventral midbrain dopaminergic neurons [28]. One would presume this to be mediated by TCF/LEF family transcription factors. However, the Nurr1 transcription factor, a well-described regulator of dopaminergic gene expression, can also be bound and co-activated by β-catenin [29]. Together, these observations demonstrate a fundamental importance for Wnt signalling in the biology of dopaminergic neurons, and also suggest the intriguing possibility that the requirement of canonical Wnt signalling could be partly due to βcatenin-dependent co-activation of Nurr1-mediated gene expression. Wnt signalling in neurodegeneration Evidence for links between perturbed Wnt signalling and neurological diseases such as schizophrenia, bipolar disorder and late-onset neurodegenerative diseases has accumulated over the last decade [6]. Indeed, in the case of AD (Alzheimer’s disease), evidence is sufficiently strong for a unifying hypothesis for the aetiology of this disease to have been made, centred around dysregulated Wnt cascades [6]. Importantly, both canonical and non-canonical Wnt pathways have been shown to be deregulated at early disease stages; however, the majority of work has focused on the canonical pathway. Notably, post-mortem brains from AD patients display increased levels of GSK3β and phosphorylated β-catenin, as well as elevated levels of Dkk1 (Dickkopf-1), a secreted protein that inhibits the canonical pathway by binding LRP6 [6,30]. The potential role of Dkk1 is supported by observations that Dkk1-neutralizing antibodies are protective against synaptic loss in mouse models of AD [31]. These observations suggest a simple mechanism whereby Dkk1 inhibits Wnt signalling at the membrane, leading to enhanced cellular GSK3β activity and increased repression of β-catenin. Tantalizingly, such a model also explains one of the major pathological hallmarks of AD, hyperphosphorylated tau protein, since GSK3β is considered to be the major kinase for tau in cells. Further links between the canonical Wnt pathway and AD come from genetics. For example, ApoE4 (apolipoprotein E4), a well-known risk factor for the development of AD, was reported to inhibit canonical Wnt signalling. Furthermore, an LRP6 variant (p.I1062V) conferring reduced Wnt signalling has been associated with late-onset AD in carriers of the ApoE4 isoform in GWASs (genome-wide association studies) [32]. The above evidence makes up-regulation, especially of canonical Wnt signalling, a promising approach for developing lead compounds for modifying pathological processes underlying AD. Wnt signalling and PD Canonical and non-canonical Wnt signalling clearly play a role in dopaminergic cell development, synaptic function and maintenance. Taken together with the established links between dysregulated Wnt signalling and neurodegeneration, it is evident that disruption of Wnt signalling pathways could also underlie the pathogenesis of PD. Direct evidence supporting this idea comes from studies into the genetic C The C 2012 Biochemical Society Authors Journal compilation 1125 1126 Biochemical Society Transactions (2012) Volume 40, part 5 Figure 2 Links between the canonical Wnt pathway and proteins linked to PD A hypothetical model connecting six proteins genetically linked to PD (shown in red) via the canonical Wnt pathway and β-catenin (β-cat)-regulated gene expression. Wnt signalling proteins shown to be required for the development of the dopaminergic neurons of the ventral midbrain are shown in purple. APC, adenomatous polyposis coli; α-syn, α-synuclein (SCNA). causes of the disease. In particular, the E3 ubiquitin ligase parkin, encoded by PARK2, has been reported to repress βcatenin by inducing β-catenin ubiquitination and degradation [33]. Parkin dysfunction therefore leads to the accumulation of β-catenin and a resultant up-regulation in canonical Wnt signalling. Rawal et al. [33] showed that β-catenin protein levels, but not mRNA levels, were increased significantly in the ventral midbrain of parkin-knockout mice compared with wild-type controls. Curiously, other brain regions investigated did not show significant changes, suggesting that this change is highly relevant to PD. The observed increase in canonical Wnt signalling in parkin-knockout mice was associated with increased levels of cyclin E and the death of primary dopaminergic neurons. This suggests a mechanism of cell death related to attempted cell cycle re-entry of postmitotic neurons. Therefore one physiological role of parkin function might be to protect dopaminergic neurons from excessive canonical Wnt signalling by inducing β-catenin ubiquitination and degradation, particularly in brain regions implicated in the pathogenesis of PD [33]. In the light of the decreased Wnt signalling described in AD, increased Wnt signalling might seem a counterintuitive pathomechanism for PD. However, elevated Wnt signalling leading to attempted cell cycle re-entry has also been reported in both human AD brains and AD mouse models. This suggests that both C The C 2012 Biochemical Society Authors Journal compilation inhibition and overactivation of Wnt signalling might play roles in neurodegeneration [34]. This supports the idea that, throughout life, Wnt signalling needs to be regulated within well-defined boundaries. LRRK2 (leucine-rich repeat kinase 2), encoded by PARK8, has also been linked to Wnt signalling pathways via protein–protein interactions with the key Wnt signalling components GSK3β and DVL [35–37]. Importantly, the interaction between GSK3β and LRRK2 is strengthened by the pathogenic LRRK2 G2019S mutation. This enhanced interaction was also reported to elicit increased tau phosphorylation [35]. Although traditionally a hallmark of AD, this observation is relevant, since tau has also been linked to PD. Typical tau pathology has been observed in post-mortem brains of patients with PARK8 mutations [38], whereas MAPT, the gene encoding tau, has been linked to PD in GWASs [39]. Further strengthening this connection, GSK3β polymorphisms discovered in PD patients were suggested to interact with tau haplotypes to modify PD risk [40]. These are important observations given the relevance of Wnt signalling to the control of tau phosphorylation by GSK3β. The DVL–LRRK2 protein interaction was also modified by PARK8 mutations, in this case in the LRRK2 ROC (Ras of complex proteins)–COR (C-terminal of ROC) LRRK2: Function and Dysfunction domain, which has intrinsic GTPase activity [36]. Further studies in differentiated SH-SY5Y cells, an in vitro model of dopaminergic neurons, revealed that LRRK2 and DVL proteins co-localize in neurites and growth cones [36]. These observations implicate LRRK2 in processes partially controlled by Wnt signalling and previously linked to PD, such as membrane trafficking and cytoskeletal rearrangements. Another connection between LRRK2 and Wnt signalling comes from investigations into the effect of LRRK2 knockdown [41]. Down-regulation of LRRK2 via siRNA (small interfering RNA) triggered altered expression of a number of Wnt pathway genes including DVL2 [41]. Although this connection is indirect, the capacity of Wnt signalling pathways to modulate the expression of their component proteins is well established. Taken together, these observations create a strong case for a role for LRRK2 in the canonical Wnt pathway, bridging DVL and GSK3β proteins. In principle, altered protein interaction strength caused by PARK8 mutations could lead to subtle changes in canonical Wnt signalling that would eventually cause a gradual loss of synaptic function. In addition, effects of LRRK2 on other Wnt cascades remain a possibility, since DVL proteins function in all three branches of Wnt signalling [3,4], and GSK3β has a role in the non-canonical/PCP pathway [42] and also modulates certain Wnt/Ca2 + effectors such as NFAT and NF-κB [43]. A mutation found in Nurr1 in an individual with PD provides another genetic link to Wnt signalling [44]. As mentioned above, the Nurr1 transcription factor is a β-catenin target, and reduced Nurr1 expression has been observed in dopaminergic midbrain neurons containing α-synucleinpositive Lewy bodies [45]. Additional evidence linking Nurr1 to PD is the finding that Nurr1 represses α-synuclein expression [46]. Thus the canonical Wnt pathway provides a mechanism connecting the PARK gene products LRRK2 and parkin with GSK3β activity, tau phosphorylation and Nurr1 activity important in PD pathogenesis. Furthermore, this pathway potentially controls the expression levels of the key PD protein α-synuclein (Figures 1 and 2). Dysregulated Wnt signalling might also play a central role in the progression of PD through brain inflammation and impaired adult neurogenesis. In particular, reactive astrocytes and microglia were shown to protect dopaminergic neurons in animal models of PD by activating canonical Wnt signalling and promoting neurogenesis from adult subventricular zone neuroprogenitor cells by a mechanism partially based on the interplay between inflammation and canonical Wnt signalling [47–49]. Conclusions In conclusion, Wnt signalling is of fundamental importance to dopaminergic ventral midbrain neurons throughout life, whereas dysregulation of Wnt pathways is well described in neurodegenerative diseases. In addition, since Wnt signalling cascades are well established in controlling cell biological functions affected during the pathogenesis of PD such as microtubule stability, axonal function and membrane trafficking [6,37], deregulated Wnt signalling represents a feasible initiating event in the pathogenesis of PD. These observations have additional implications for PD treatment. Modulation of Wnt signalling is likely to be of significant importance for complete dopaminergic specification of human embryonic stem cells for transplantation [50]. The development of targeted methods for regulating Wnt signalling might also be considered as a strategy for the development of new PD-modifying therapies in the future [6]. At the very least, such treatments will support physiological synapse function, adult neurogenesis and responses to inflammatory processes. However, as we have outlined, modulators of Wnt signalling may also be able to reverse the underlying signalling defect with the potential to slow or halt disease progression and provide more than the currently available symptomatic treatment for PD. Funding We are grateful for the support of our work on PD and Wnt signalling by the Wellcome Trust [grant numbers WT088145MA and WT095010MA (to K.H.)] and the Michael J. Fox Foundation (to D.C.B. and K.H.). References 1 Gasser, T. (2009) Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev. Mol. Med. 11, e22 2 MacDonald, B.T., Tamai, K. and He, X. (2009) Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 3 Gao, C. and Chen, Y.G. (2010) Dishevelled: the hub of Wnt signaling. Cell. Signalling 22, 717–727 4 Wallingford, J.B. and Habas, R. (2005) The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. 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