Available online at www.sciencedirect.com
Behavioural Brain Research 189 (2008) 350–356
Research report
Memory and exploratory impairment in mice that lack the Park-2
gene and that over-express the human FTDP-17 mutant Tau
Paloma Navarro a , Rosa Guerrero a , Eva Gallego a , Jesus Avila b ,
Rosario Luquin c , Pedro J. Garcia Ruiz a , Marina P. Sanchez a,∗
a
Fundacion Jimenez Diaz-Capio/Clinica Ntra. Sra. Concepcion, Universidad Autonoma de Madrid, 28040 Madrid, Spain
b Centro de Biologia Molecular “Severo Ochoa”, CSIC/Universidad Autonoma de Madrid, Spain
c Centro de Investigaciones Médicas Aplicadas, Universidad de Pamplona, Navarra, Spain
Received 8 August 2007; received in revised form 17 January 2008; accepted 24 January 2008
Available online 5 February 2008
Abstract
While mutations in the Park-2 gene are the most frequent cause of autosomal-recessive juvenile parkinsonism (AR-JP), they are also present
in several forms of tauopathies. Conversely, in some forms of parkinsonism, mutations in the tau gene have also been observed. Deletion of the
Park-2 gene and over-expression of mutant tau independently produce mild brain alterations in mice. However, the presence of both mutations
simultaneously causes a tau neuropathology, involving reactive astrocytosis, neuron loss in the cortex and hippocampus, and lesions in nigrostriatal
and motor neurons. Furthermore, mutant tau over-expression in mice produces important memory impairment. When “parkin” function was
abolished in young tau transgenic mice, the memory alterations were exaggerated. Moreover, additional exploratory and motor deficits were
observed in older mice, causing the memory alterations to be underestimated. Thus, while memory deficits are more severe in young mice they
were somehow attenuated by exploratory impairments in ageing mutants. This double mutant animal will serve as a useful experimental tool to
investigate the abnormal processing of hyperphosphorylated tau and its relationship to the development of the cognitive deficits associated with
certain neurodegenerative diseases.
© 2008 Elsevier B.V. All rights reserved.
Keywords: Parkin; Park-2 gene deletion; Human tau transgene; FTDP tau mutations; Mouse model; Object recognition task; Memory alterations
1. Introduction
The Park-2 gene encodes the ubiquitin protein ligase
parkin that is implicated in proteasome-dependent protein
degradation [47]. Loss-of-function mutations in the Park-2
gene cause autosomal-recessive juvenile parkinsonism (ARJP), one of the most common forms of familial parkinsonism
[1,18,25,28,32,56,57] that is characterized by a selective loss of
dopaminergic neurons in the substantia nigra without the appearance of Lewy bodies [19,35,56,57]. Single parkin mutations
have been detected in patients with Parkinson’s disease (PD)
[58], while mutations in the Park-2 gene have also been found
∗ Corresponding author at: Laboratory of Neurology, Fundacion Jimenez
Diaz-Capio/Clinica Ntra. Sra. Concepción, Av Reyes Catolicos 2, 28040 Madrid,
Spain. Tel.: +34 91 5504800x3251; fax: +34 91 5497700.
E-mail address: msanchezg@fjd.es (M.P. Sanchez).
0166-4328/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbr.2008.01.017
in patients with certain tauopathies [34,43]. Conversely, mutations in the gene encoding the microtubule-associated protein
tau have been reported in other forms of familial parkinsonism
and dementia [49]. Indeed, missense mutations of the tau gene
cause autosomal-dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) [20,41,50], and tau
aggregates are also present in some other cases of autosomaldominant parkinsonism [59]. However, mutations in the tau gene
have not been observed in the most frequent cases of tauopathies
[52]. Moreover, several cases of dementia have been reported
where mutations in Park-2 appear in conjunction with a tau
protein pathology [34,35,56]. Thus, parkin may be functionally related to tau, and the combination of both parkin and tau
mutations may trigger functional deficits, possibly related to the
processing and degradation of anomalous hyperphosphorylated
tau protein [26,40,43]. Moreover, abnormal parkin activity may
contribute to the development of tauopathies in individuals with
genetic risk factors [34,43].
P. Navarro et al. / Behavioural Brain Research 189 (2008) 350–356
Neurofibrillary tangles (NFTs) are neuronal inclusions that
are composed of modified hyperphosphorylated tau protein,
which has a low affinity for tubulin and a high tendency to selfassemble [3,6,10,11,16,22]. Clearance of the tau aggregates is
mediated by the proteasome [55] and it is dependent on the phosphorylation state of tau [27]. In Alzheimer’s disease (AD), NFTs
occur in the hippocampus, amygdala, the entorhinal and other
association cortices, as well as in the basal forebrain. These
brain areas are severely affected by the loss of neurons and
synapses that contribute to the cognitive deficits and dementia in AD [5,12,46,59]. Transgenic mice and gene-targeting of
Tau are valuable models to study these conditions, as they reproduce various aspects of tauopathies and AD tau pathology with
associated cognitive changes [2,8,13–15,21,29,38,44,53,54].
Deletion of the parkin gene in Park− mice alters protein
degradation and dopamine neurotransmission, without a loss of
nigral dopaminergic neurons [24]. In FTDP-17 TauVLW mutant
mice, the hTauVLW transgene is expressed in the cytoplasm
and dendrites of cortical and hippocampal neurons, as well as
in other brain regions not relevant to AD [30]. Furthermore,
there is an age-dependent appearance of hyperphosphorylated
tau filaments in mutant FTDP-17 tau-positive neurons, with the
appearance of pretangles [30]. We generated a double mutant
mouse (Park− /TauVLW ) that over-expresses a human FTDP-17
mutant four-repeat form of tau, the hTauVLW transgene, and that
is also deficient in the Park-2 gene [17]. These mice develop normally, although their survival is considerably curtailed. The lack
of the parkin protein in young TauVLW mice produces an accumulation of AT8 and PHF-1 hyperphosphorylated tau in cortical
and hippocampal neurons. However, while the product of the
hTauVLW transgene is found in both cell bodies and dendrites
in young transgenic mice, it is only detected in the cell bodies of
neurons when the Park-2 gene is deleted. Closer analysis of the
Park− /TauVLW mouse brain indicates that either the subcellular
distribution of the hTauVLW transgene product or its level of
expression differs from that in the TauVLW mouse. Thus, in the
absence of parkin, the mutant tau is excluded from the dendrites
and it is restricted to the cytoplasm of neurons. Additionally, the
presence of reactive astrocytes in these double mutants is associated with an increase in glial fibrillary acidic protein (GFAP)
expression. Although very few apoptotic neurons were detected
in single TauVLW mice, neuron loss is evident in the cortex and
hippocampus of young Park− /TauVLW mice [17]. Moreover, in
cortical and hippocampal extracts from double Park− /TauVLW
mutants the expression of the neuroprotective heat shock protein 70 (Hsp70) was accentuated while the carboxyl-terminus
of the Hsp70-interacting protein (CHIP) was depleted, a ubiquitin protein ligase known to attenuate the aggregation of tau
[42] and to enhance the ubiquitination of phosphorylated tau
[39,48]. When these animals died at the age of 14 months old,
most neurons lacked tau and displayed a degenerated cytoplasm
and condensed nuclei [17]. In addition, behavioural studies of
Park− /TauVLW mice showed mild changes in motor activity
(manuscript in preparation).
Here, we have investigated the effect that the alterations
in the brain of these Park− /TauVLW mice has on memory.
Accordingly, we found that young animals over-expressing the
351
hTauVLW transgene develop severe memory deficits that were
more pronounced when the Park-2 gene was deleted. Moreover, ageing double mutant mice present an additional defect
in exploratory performance that could mask the expression of
the more important memory impairments. These results further reflect the existence of a functional interaction between the
parkin and tau proteins.
2. Methods
2.1. hTauVLW transgenic and parkin-null double mutant mice
The human hTauVLW transgenic mouse line (TauVLW ) that over-expresses
a four-repeat human tau isoform with the FTDP-17 mutations G272V, P301L
and R406W has been described elsewhere [30]. The Parkin-deficient mice were
generated by gene targeting of the Park-2 gene in embryonic stem cells [24].
Subsequently, we obtained Park− , TauVLW , Park− /TauVLW by breeding TauVLW
mice with Park− or wild type mice on the same C57BL/6J genetic background
[17]. All the experiments carried out on these mice were previously approved
by the Animal Investigation Committee at our Institution.
2.2. Expression of mutant proteins in Western blots
Protein extracts were prepared from brain homogenates in the presence of a
protease inhibitor cocktail (Boehringer Manheim). Protein samples were separated on SDS-polyacrylamide gels, electroblotted onto nitrocellulose sheets, and
incubated with specific antibodies that were detected by ECL (Amersham). The
antibodies used to assess the expression of mutant proteins included: a parkin
polyclonal antiserum directed against a peptide corresponding to residues 71–91
of mouse parkin [24]; T14 (Zymed Laboratories, INC), an antibody that recognises an epitope present in human tau protein but that is absent in endogenous
murine tau; and the 7.51 antibody (a kind gift of Dr. C.M. Wischick, MRC,
Cambridge, UK) that recognizes a phosphorylation-independent epitope at the
carboxy-terminal region of human and murine tau molecules.
2.3. Object recognition task (ORT)
We used the ORT to measure episodic memory retention in groups of young
and adult mice. After a 10 min session of adaptation to an empty dark box, the
time employed in exploring (tA and tB ) two equivalent objects (objects A and B)
was measured for each mouse in the sample familiarisation phase. Mice whose
total exploration time was ≤3 s were eliminated for the rest of the test. The test
phase was then performed 2 h later, and the times (tA and tC ) the animal spent
exploring two objects were recorded, the familiar object (A) and a novel object
(C). Mice with a total exploration time ≤1 s per object in the test phase were
also eliminated and the percentage time exploring objects A and C was then
represented for the single and double mutant mice. A discrimination index (DI)
was calculated as the ratio of the difference between the exploration times of the
new (tC ) and the old familiar object (tA ), with respect to the total (tT ) exploration
time as follows: DI = tC − tA /tT .
2.4. Statistical analysis
Two groups of male animals were analyzed at 6–8 and 15–17 months of
age, as representative samples of adult and aged mice. Initially, the number of
animals in each group was 12–26. The values are expressed as means ± S.E.M.
and the statistical evaluation was performed by one way-ANOVA followed by
post hoc Newman–Keuls test (GraphPad Prism 2.0). Statistical significance was
considered when p < 0.05.
3. Results and discussion
Several cases of tauopathies have been reported in patients
carrying mutations in the Park-2 gene while conversely, muta-
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P. Navarro et al. / Behavioural Brain Research 189 (2008) 350–356
tions in the tau gene have been detected in patients with
certain types of parkinsonism. Thus, parkin may be functionally
related with tau, probably in the processing and degradation of
hyperphosphorylated forms of the tau protein [26,39,43]. We
described a patient who was carrier of a single mutation in the
Park-2 gene, and who was homozygous for the H1/H1 haplotype
in the tau gene, a risk haplotype for progressive supranuclear
palsy [34,43]. Neuropathological studies on this patient identified tau aggregates and abnormal hyperphosphorylation of tau in
these aggregates, suggesting that a partial deficit of parkin may
trigger a tau pathology in individuals with molecular genetic risk
factors [43]. This led us to postulate that parkin plays a role in the
intracellular processing of tau and that abnormal parkin function
may be a risk factor for the development of tauopathies. To test
this possibility we generated a double mutant mouse in which
the Park-2 gene was deleted [24] in conjunction with the presence of the human TauVLW transgene [30], the Park− /TauVLW
mouse [17].
In the absence of parkin, there were mild nigrostriatal
and motor neuron lesions in the hTauVLW transgenic mice
[33]. Moreover, hyperphosphorylated tau aggregates with AT-8
(Fig. 1A) and PHF1 were detected [17], and GFAP immunostaining identified reactive astrocytes in the cortex and hippocampus
(B). DNA fragmentation and a varying degree of cerebral atrophy were also observed in these regions [17]. Additionally, the
expression of GFAP, Hsp70 and CHIP was altered in protein
extracts from these animals [17]. The absence of parkin protein in single Park− and double Park− /TauVLW mutants was
demonstrated in Western blots (C). Similarly, immunoblotting
with the T14 antibody, which recognizes an epitope present
in the human mutant tau, and with 7.51 that recognizes a
phosphorylation-independent epitope at the carboxy-terminal
region of human and murine tau molecules, revealed the existence of the two forms of tau in the brains of single TauVLW and
double Park− /TauVLW mutant mice (C).
We studied the functional effects of the Park-2 gene deletion
in TauVLW transgenic mice in a memory performance test. Two
groups of male animals were analyzed at 6–8 and 15–17 months
of age and the effects of the mutations on the episodic memory of our mice were studied by measuring object recognition
Fig. 1. Expression of AT8 phosphorylated tau, GFAP, parkin, and endogenous murine and human mutant tau in the cerebral cortex and hippocampus of Park− /TauVLW
mice. AT8 immunoreactive tau aggregates are shown in some scattered neurons of the anterior frontal cortex of 14-month-old Park− /TauVLW mice (A). Reactive
gliosis, identified with GFAP antibody, is shown in the dentate gyrus of double mutants at the same age (B). Representative Western blots of protein extracts from
the cortex of wild type (1), Park− (2), TauVLW (3) and Park− /TauVLW (4) mice probed with the T14, 7.51 and parkin antibodies (C). Scale bar corresponds to 40 m
in (A) and to 60.4 m in (B).
P. Navarro et al. / Behavioural Brain Research 189 (2008) 350–356
learning in the ORT. The total exploration times of equivalent
objects in the sample phase were measured in the three mutant
mouse lines: Park− , TauVLW , Park− /TauVLW . At 6–8 months of
age, the total exploration time in the sample phase for objects
A and B was significantly higher in Park− mice than in wild
type mice and those over-expressing the hTauVLW transgene
(Fig. 2A). The percentage time that the three mutant groups of
mice spent exploring objects A and B in this phase was similar to that of the wild type mice (B). By contrast, in the test
phase the total exploration time of Park− mice of the familiar
(A) and novel (C) objects was significantly higher than that of
wild type mice and those over-expressing the hTauVLW transgene (C). Moreover, the Park− mice explored the novel object
(C) longer than the familiar one (A) during the test phase, like the
wild type animals (D). However, the over-expression of hTauVLW induced a failure to discriminate between the novel and
the familiar objects (D), indicating the existence of deficits in
the retention of episodic memory when the hTauVLW transgene is over-expressed. In accordance, the discrimination index
decreased when hTauVLW was over-expressed and this alteration was slightly more pronounced when Park-2 gene was also
deleted (E).
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At 15–17 months of age, the total exploration time of TauVLW
and Park− /TauVLW mice in the sample phase (objects A and B)
was less than that of Park− and wild type mice (Fig. 3A). However, this difference was only statistically significant when compared to Park− mice, since deletion of the Park-2 gene produced
a mild additional increase in the object exploration time (A). A
small number of Park− /TauVLW animals explored the objects in
the sample phase, although there was no difference in the percentage time they spent exploring objects A and B (B). A deficit
was observed in object recognition memory in the TauVLW and
Park− /TauVLW mice, reflected by the similar proportion of time
they spent exploring objects A and C (D). Indeed, there was a
decrease in the discrimination index in the three mutant groups
when compared to the wild type animals (E), although this difference was only statistically significant for the TauVLW mice. In
the aged Park− /TauVLW mice, the failure to detect a significant
decrease was probably due to the limited number of animals that
displayed exploratory behaviour during the test phase. Indeed,
deletion of the Park-2 gene produced an increase in locomotor activity of both single and double Park− /TauVLW mice
(manuscript in preparation). Interestingly, Park− mice showed a
significant increase in object exploration time in the ORT, prob-
Fig. 2. Analysis of episodic memory using the object recognition task (ORT) on young mice (6–8 months of age). Initially, 14, 12, 19 and 26 animals were analyzed
from the wild type, Park− , TauVLW and Park− /TauVLW groups, respectively. (A) Total exploration time (tA + tB ) of two equal objects (objects A and B) in the sample
phase, after the elimination of animals with a total exploration time ≤3 s. The numbers of mice finally analyzed in the sample phase were n = 9, 12, 15 and 23 for
wild type, Park− , TauVLW and Park− /TauVLW mouse lines, respectively. (B) Percentage exploration of objects A and B in the sample phase. (C) Total exploration
time (tA + tC ) of two different objects (A and C) in the test phase. The number of animals of the final groups in the test phase were n = 6, 11, 12 and 15 from wild
type, Park− , TauVLW and Park− /TauVLW mouse lines, respectively. (D) Percentage time exploring two different objects (objects A and C) in the test phase after the
elimination of animals with a total exploration time ≤1 s per object. (E) The DI was calculated as the ratio of the difference between the exploration times of the
new (tC ) and the familiar object (tA ), and the total (tT ) exploration time (DI = tC − tA /tT ). Values are expressed as mean ± S.E.M. One way-ANOVA followed by
Newman–Keuls tests were performed. *p < 0.05, **p < 0.01, ***p < 0.001.
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P. Navarro et al. / Behavioural Brain Research 189 (2008) 350–356
Fig. 3. Analysis of episodic memory in mice aged (15–17 months of age) using the object recognition task. Initially, we analyzed 16, 15, 14 and 9 animals from the
wild type, Park− , TauVLW and Park− /TauVLW groups, respectively. In the sample phase, after elimination of the animals with a total exploration time ≤3 s, 14, 14,
12 and 6 mice were analyzed from the wild type, Park− , TauVLW and Park− /TauVLW mouse lines, respectively. (A) Total exploration time (tT ) in the sample phase.
(B) Percentage exploration times of objects A and B in the sample phase. (C) Total exploration time in the test phase. (D) Percentage time exploring two different
objects (objects A and C) in the test phase after the elimination of animals with a total exploration time ≤1 s. The final number of animals used in the test phase
were n = 13, 14, 9 and 4 from wild type (81.25%), Park− (93.3%), TauVLW (64.2%) and Park− /TauVLW (44%) mouse lines, respectively. (E) The DI is the ratio of
the difference between the exploration times of the new (tC ) and the familiar object (tA ), and the total (tT ) exploration time (DI = tC − tA /tT ). Values are expressed as
mean ± S.E.M. Statistical analysis was performed by one way-ANOVA followed by Newman–Keuls tests. *p < 0.05; **p < 0.01.
ably as a consequence of their hyperactivity. However, while
Park− /TauVLW mice moved around the cage and were active,
they spent less time exploring the objects and most of them, the
most affected population, had to be excluded from the test.
It has been reported that a significant number of tau transgenic mouse models present neurofibrillary pathology, neuronal
loss and memory deficits [2,4,13,15,23,38,44,45]. Moreover,
improved animal models for neurodegenerative disorders have
been generated by combining mutations of genes that interact in
different pathways [7,9,14,29,31,36,37,51]. However, none of
these mouse models generated to date fully recapitulate the neuropathological spectrum of tangle pathology observed in AD.
The Park− /TauVLW mutant mice that we have produced will
help us investigate the relationship between parkin and tau proteins in the development of tau pathology and the functional
consequences of these alterations. The deletion of parkin alone
did not produce any effect on memory performance in mice,
while human mutant tau over-expression produced severe memory impairments. However, the combination of both parkin and
tau mutations gives rise to a stronger memory impairment in
young mice, although this effect is diminished in older mice,
probably due to some exploratory and/or motor deficits that
precede their premature death. The presence of tau aggregates
in the cortex and hippocampus of young mice lacking parkin
and those that over-express human mutant tau [17] could be the
responsible for the increased memory impairment. The absence
of parkin could interfere with the binding of tau to microtubules
and as such, this may increase the availability of free cytosolic tau which is more susceptible to phosphorylation. Hence,
parkin is probably implicated in the processing and degradation of hyperphosphorylated forms of the tau protein, although
this process does not involve a direct interaction between the
two proteins. Moreover, the existence of lesions in nigrostriatal and motor neurons at early ages [33] could be associated to
the presence of motor disturbances that might interfere with the
interpretation of the data obtained in the memory test. Further
behavioural studies are now in progress to test this possibility.
Nevertheless, the mouse model that we have generated is a useful
tool to study the role played by the parkin ubiquitin ligase in the
degradation of hyperphosphorylated tau, and in the ensuing formation of tau aggregates. Further studies of these mutants will
hopefully help us to understand the mechanisms responsible for
the memory impairments developed in some neurodegenerative
diseases that are related to the tau and parkin proteins.
P. Navarro et al. / Behavioural Brain Research 189 (2008) 350–356
Disclosure statement
All the authors state that there are no actual or potential
conflicts of interest including any financial, personal or other
relationships with individuals or organizations that could inappropriately influence our work.
Acknowledgments
The authors would like to thank Drs. Jeremy Park, Jesus
Benavides, and Filip Lim for the use of Park− and TauVLW
mice, and Drs. Francisco Wandosell and Javier Dı́az-Nido for
critical reading of the manuscript. We are also grateful to the
Animal Facility of the Fundación Jiménez Dı́az-Capio, especially to M. Luisa Valbuena, for technical support. This work
was supported by a grant from the Fondo de Investigaciones
Sanitarias. MPS was supported by the Instituto de Salud Carlos
III and FJD-Capio, and PN was supported by a fellowship from
the Fundación Conchita Rábago.
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