Mutations in the LRRK2 Roc-COR tandem
domain link Parkinson’s disease to Wnt
Rosa M. Sancho, Bernard M.H. Law and Kirsten Harvey?
Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London, UK
Received June 9, 2009; Revised and Accepted July 20, 2009
Mutations in PARK8, encoding LRRK2, are the most common known cause of Parkinson’s disease. The
LRRK2 Roc-COR tandem domain exhibits GTPase activity controlling LRRK2 kinase activity via an intramo-
lecular process. We report the interaction of LRRK2 with the dishevelled family of phosphoproteins (DVL1-3),
key regulators of Wnt (Wingless/Int) signalling pathways important for axon guidance, synapse formation
and neuronal maintenance. Interestingly, DVLs can interact with and mediate the activation of small
GTPases with structural similarity to the LRRK2 Roc domain. The LRRK2 Roc-COR domain and the DVL1
DEP domain were necessary and sufficient for LRRK2–DVL1 interaction. Co-expression of DVL1 increased
LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. Strikingly, LRRK2–
DVL1-3 interactions were disrupted by the familial PARK8 mutation Y1699C, whereas pathogenic mutations
at residues R1441 and R1728 strengthened LRRK2–DVL1 interactions. Co-expression of DVL1 with LRRK2 in
mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293
and SH-SY5Y cells and co-localization in neurites and growth cones of differentiated dopaminergic SH-SY5Y
cells. This is the first report of the modulation of a key LRRK2-accessory protein interaction by PARK8 Roc-
COR domain mutations segregating with Parkinson’s disease. Since the DVL1 DEP domain is known to be
involved in the regulation of small GTPases, we propose that: (i) DVLs may influence LRRK2 GTPase activity,
and (ii) Roc-COR domain mutations modulating LRRK2–DVL interactions indirectly influence kinase activity.
Our findings also link LRRK2 to Wnt signalling pathways, suggesting novel pathogenic mechanisms and new
targets for genetic analysis in Parkinson’s disease.
The PARK8 locus encodes LRRK2, a 2527 amino acid cytoso-
lic protein kinase. Mutations in PARK8 are the most common
known cause of Parkinson’s disease, with missense mutations
found in patients with familial as well as apparently idiopathic
Parkinson’s disease (1–5). LRRK2 belongs to the ROCO
family of proteins which are characterized by the unique com-
bination of a Roc (Ras of complex proteins) domain with
intrinsic GTPase activity and a COR (C-terminal of Roc)
domain. The Roc-COR tandem domain controls LRRK2
kinase activity via an intramolecular process (6–12). The
modification of LRRK2 GTPase and kinase activity by
PARK8 mutations affecting residues in the Roc, COR and
kinase domains is believed to lead to neuronal cell death,
but the pathways involved remain elusive (1,2,7,8,11–16).
The combination of GTPase activity mediated via the
Roc-COR tandem domain and kinase activity of the mitogen-
activated protein kinase kinase kinase domain suggests a
complex role for LRRK2 in cell signalling. Additional
protein–protein interaction domains, such as LRR (Leucine
rich repeat) and WD40 propeller motifs provide additional
complexity and could potentially localize LRRK2 to different
subcellular compartments. The Roc domain shares sequence
similarity with all five subfamilies of the Ras-related super-
family of small GTPases (Ras, Rho, Rab, Sar/Arf and Ran),
?To whom correspondence should be addressed at: Department of Pharmacology, The School of Pharmacy, London WC1N 1AX, UK. Tel: þ44
2077535888; Fax: þ44 2077535902; Email: email@example.com
# 2009 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is
Human Molecular Genetics, 2009, Vol. 18, No. 20
Advance Access published on July 22, 2009
has conserved amino acids involved in GTP binding/hydroly-
sis and exhibits intrinsic GTPase activity. Evidence suggests
that the COR domain forms dimers, resulting in juxtaposition
of the associated Roc domains (10). Since the isolated LRRK2
kinase domain was shown to be catalytically inactive (16,17),
it is clear that the Roc and COR domains are vital for kinase
activity and/or protein stabilization. One current theory
suggests that mutations in the Roc and COR domains
reduce GTPase activity, leading to higher kinase activity.
This suggestion is based on reports that the R1441C/
R1441G substitutions in the Roc domain reduce GTPase
activity (9,10,14,15), whereas these mutations as well as
the Y1699C mutation in the COR domain increase kinase
Thus, the LRRK2 Roc domain is likely to serve as a mol-
ecular switch, regulating kinase activity by cycling between
GDP-bound and GTP-bound states (6–17). However, it is cur-
rently unclear how this activity is controlled in vivo. Normally,
guanine nucleotide exchange factors (GEFs) facilitate GTP
binding and effector activation, whereas GTPase-activating
proteins (GAPs) increase the intrinsic rate of GTP hydrolysis
to terminate signalling (18). Interestingly, the GTPase activity
of a Roc-COR tandem domain from Chlorobium tepidum, a
prokaryotic homologue of LRRK2, shows a low affinity for
nucleotide and fast GDP dissociation, suggesting that
LRRK2 may not require a classical RhoGEF for GTPase
activity (10). Rather, Roc GTPase activity was proposed to
be stimulated solely by COR dimerization. However, this
model seems simplistic, as it would not allow for up- or down-
regulation of GTPase and kinase activity. Thus, the identifi-
cation of proteins involved in regulating LRRK2 GTPase
activity and mediating downstream signalling is of fundamen-
tal importancein understanding
Parkinson’s disease. Since the Roc-COR tandem domain con-
trols LRRK2 kinase activity, we searched for interactors of the
Roc-COR domain with likely relevance for GTPase and kinase
activity. Here, we describe the discovery and characterization
of the interaction of LRRK2 with all members of the dishev-
elled (DVL) family of phosphoproteins in yeast and mamma-
lian cell systems. DVLs have a modular architecture
consisting of DIX (Dishevelled/Axin), PDZ (PSD-95, DLG,
ZO1) and DEP (Dishevelled, EGL-10, Pleckstrin) domains.
Importantly, DVL proteins are key regulators of Wnt signal-
ling pathways leading to multiple downstream effects (19),
including the activation of small GTPases such as Rac1 that
are structurally similar to the LRRK2 Roc domain (20).
Recent studies have underlined the importance of DVLs in
key processes in neuronal development, such as axon gui-
dance, synapse formation and neuronal maintenance (19,21–
27). The identification of DVL proteins as interactors of
LRRK2 suggests a plausible physiological role for LRRK2
in these processes. DVL proteins altered the subcellular distri-
bution of LRRK2 and co-localized in neurites and growth
cones of differentiated dopaminergic SH-SY5Y cells. The
LRRK2-DVL1 interaction stabilizes steady-state levels of
LRRK2, but importantly LRRK2-DVL interactions are
decreased or increased by selected PARK8 Roc-COR domain
mutations segregating with Parkinson’s disease.
Further functional characterization of LRRK2-DVL inter-
encountered in purifying intact DVL proteins, reproducibility
and sensitivity of LRRK2 GTPase and kinase assays, and
the lack of commercially available antibodies against
LRRK2 and DVL1-3 proteins that function in immunoprecipi-
tation experiments. Nonetheless, the dissemination of our
results to a wider audience at this stage will highlight valuable
leads for further research into the endogenous control of
LRRK2 GTPase and kinase activity. We also suggest the rel-
evance of Wnt signalling pathways to Parkinson’s disease,
underpin the importance of microtubule dynamics in neurode-
generation (28–34) and identify DVL proteins as therapeutic
and genetic targets for future therapeutic and genetic research.
LRRK2 associates with DVL family proteins
via a Roc-COR–DEP domain interaction
In order to identify LRRK2 accessory proteins potentially
regulating kinase activity, we screened an embryonic
human brain cDNA library (Clontech) using the LexA yeast
tandem domain (Roc-COR) as ‘bait’. This resulted in the
identification of several overlapping partial cDNAs encoding
DVL2 and DVL3, members of the dishevelled family of
phosphoproteins (Fig. 1A), which contain single DIX, PDZ
and DEP domains. None of the encoded proteins harboured
an intact DIX domain, suggesting that this motif was not
necessary for LRRK2 binding. Q-PCRs confirmed that
DVL1–DVL3 transcripts are detectable in the adult human
brain, including the substantia nigra (Supplementary Material,
Fig. S1). DVLs were considered promising candidates for
further analysis since they are known to interact with and
mediate the activation of small GTPases, such as Rac1 and
RhoA. Interestingly, the DVL1/DVL2 DEP domain alone is
sufficient for Rac1 activation, whereas both PDZ and DEP
domains are required for RhoA activation (20,35). Further
analysis demonstrated that LRRK2 interacts with full-length
DVL1-3 proteins in yeast (Fig. 1A) and HEK293 cells, as
demonstrated by co-immunoprecipitation of myc-tagged
LRRK2 and FLAG-tagged DVL constructs (Fig. 1B). It is
also noteworthy that the DVLs appear to differ in the
nature of their interaction with LRRK2. Although the
Roc-COR bait demonstrated an interaction with all three full-
length DVL proteins (DVL1-3; Fig. 1A), the interaction
between the LRRK2 Roc-COR domain and DVL1 was con-
sistently weaker compared with DVL2 or DVL3 (Fig. 1A).
However, deletion constructs lacking the N-terminal DVL1
DIX domain (DVL1DDIX) showed a robust interaction
with the Roc-COR bait, equivalent to DVL2 or DVL3
(Fig. 1A). Expressing selected subdomains or deletions of
DVL1 in yeast (Fig. 2A) or HEK293 cells (Fig. 2B) demon-
strated that removal of the DIX and/or PDZ domains did not
abolish DVL interactions with the LRRK2 Roc-COR tandem
domain, whereas constructs lacking the DEP domain were no
longer associated with LRRK2 (Fig. 2A and B). Hence,
DVL1 is capable of interacting with the LRRK2 Roc-COR
region in yeast and mammalian cells via the DEP domain,
which can interact with and mediate the activation of small
GTPases such as Rac1 (20).
3956Human Molecular Genetics, 2009, Vol. 18, No. 20
Supplementary Material is available at HMG online.
K.H. thanks Dr Mark R. Cookson and Professor Robert
J. Harvey for constructive comments and suggestions on the
Conflict of Interest statement. None declared.
This work was supported by grants from the Royal Society, the
British Medical Association (Dawkins and Lawson award) and
the Wellcome Trust (WT088145) to K.H. and two School of
Pharmacy PhD studentships. The funders had no role in
study design, data collection and analysis, decision to
publish or preparation of the manuscript. Funding to pay the
Open Access publication charges for this article was provided
by The School of Pharmacy.
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