Download The importance of Wnt signalling for neurodegeneration in

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
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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
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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
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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
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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.).
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Received 2 May 2012
doi:10.1042/BST20120122