MINIREVIEW
Parkinson’s disease: genetic versus toxin-induced rodent
models
Mu
¨
gen Terzioglu
1
and Dagmar Galter
2
1 Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
2 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Introduction
Parkinson’s disease (PD) is a common neurodegenera-
tive disease with a complex etiology resulting from
genetic factors, environmental exposures, or a combi-
nation of both.
The clinical key symptoms are motor dysfunctions
such as bradykinesia, resting tremor and muscle
rigidity combined with postural instability, but many
patients also suffer from autonomic and cognitive dis-
turbances. Selective degeneration of dopamine neurons
in the substantia nigra (SN) causes the major PD
symptoms, but there is often widespread neurodegener-
ation and pathology in other regions of the brain,
including the proteinaceous inclusions called Lewy
bodies (LBs) and dystrophic neurites called Lewy
neurites. By the time clinical manifestations appear,
about 60–70% of the dopamine fibers in the caudate
Keywords
6-OHDA; conditional knockout mice;
DAT-cre; dopamine system; Engrailed;

review will focus on the comparison of three types of rodent animal models
used to study different aspects of PD: (a) animal models using neurotoxins;
(b) genetically modified mouse models reproducing findings from PD link-
age studies or based on ablation of genes necessary for the development
and survival of dopamine neurons; and (c) tissue-specific knockouts in mice
targeting dopamine neurons. The advantages and disadvantages of these
models are discussed.
Abbreviations
6-OHDA, 6-hydroxydopamine; cre, cre-recombinase; DA, dopamine; DAT, dopamine transporter; En, Engrailed; IR, immunoreactive; LB,
Lewy body;
L-dopa, L-3,4-dihydroxyphenylalanine; LRRK2, leucine-rich repeat kinase 2; MAO-B, monoamine oxidase B; MPP
+
, 1-methyl-4-
phenyl-2,3-dihydropyridium ion; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease; PINK1, PTEN-induced kinase 1;
ROS, reactive oxygen species; SN, substantia nigra; TFAM, mitochondrial transcription factor A; TH, tyrosine hydroxylase; VMAT, vesicular
monoamine transporter; VTA, ventral tegmental area.
1384 FEBS Journal 275 (2008) 1384–1391 ª 2008 The Authors Journal compilation ª 2008 FEBS
putamen and at least 50% of the dopamine neurons in
the SN are already lost. Although slow in most cases,
progression of the disease is irreversible, and different
drug treatments ameliorate symptoms without arrest-
ing or slowing down the pace of neurodegeneration.
In order to understand the underlying mechanisms
and to develop new drugs or therapies for PD, it is
important to have available animal models that reca-
pitulate key symptoms and the slow progression of the
disease as accurately as possible. Because the disease is
not known in any animal species, except perhaps mild
parkinsonism in aged nonhuman primates in captivity,
different models have been developed in several species

eral intracerebral injections of 6-OHDA followed by
chronic l-3,4-dihydroxyphenylalanine (l-dopa treat-
ment [5,6,6a].
In 1982, an analog of the narcotic drug meperidine
was accidentally discovered to be a potent dopamine
neurotoxin when young drug addicts developed irre-
versible and severe PD symptoms following self-admin-
istration of what they hoped to be synthetic heroin [7].
The highly lipophilic substance that they had synthe-
sized, MPTP, crosses the blood–brain barrier easily
after systemic administration and is converted into the
active toxic metabolite 1-methyl-4-phenyl-2,3-dihydro-
pyridium ion (MPP
+
) by the enzyme monoamine oxi-
dase B (MAO-B), located mainly in serotoninergic
neurons and astrocytes. The metabolite MPP
+
is selec-
tively taken up into dopamine neurons by the DA
transporter (DAT), and irreversibly inhibits complex I
ABC
Fig. 1. Schematic illustration of different rodent models of PD. (A) Toxin-induced models: the four different toxins penetrate dopamine neu-
rons either specifically via DAT (6-OHDA and MPP
+
) or through diffusion (rotenone and paraquat) and inhibit complex I of the mitochondrial
electron transfer chain (consisting of complex I to complex V), leading to mitochondrial intoxication with enhanced production of ROS and
reduced production of ATP. Although all toxins do not exclusively act on dopamine neurons, they induce PD symptoms and key pathology,
indicating an increased susceptibility of the DA system to mitochondrial dysfunction. (B) Genetic models: on the basis of the PD-linked
genes a-Synuclein, Parkin, Pink1, DJ-1 and LRRK2, several mouse models have been generated in which all cells of the organism are

of electrons from complex I to ubiquinone in the mito-
chondrial electron transfer chain. Rotenone interferes
with mitochondrial function at the same site as
MPP
+
, but is only mildly toxic for humans and highly
unstable, with a short half-life in the environment. In
rodents, particularly in rats, chronic infusion can
induce a slowly progressing neurodegeneration of
dopamine neurons associated with intracellular multi-
form a-synuclein immunoreactive (IR) aggregates,
occurrence of widespread oxidatively modified DJ-1,
and proteasomal impairment [13]. However, the rote-
none model has low reproducibility, and many animals
die from acute toxicity, unrelated to central nervous
system involvement.
A further rodent toxin-induced model has been
proposed that uses systemic administration of the
proteasomal inhibitor epoxomicin [14]. In this PD
model, rats reproduced most of the key features of PD
pathology, including reduced amounts of dopamine
fibers in the striatum, and degeneration of dopamine
neurons in the SN accompanied by inflammation and
intracellular aggregates with a-synuclein- and ubiqu-
itin-like immunoreactivity. However, in a further inde-
pendent study, systemic administration of epoxomicin
failed to be effective in rats or monkeys [15], although
intracerebral injection of epoxomicin and other prote-
asomal inhibitors blocked MPP
+

triplication detected in PD families, or the PD-causing
a-Synuclein mutations A30P or A53T are expressed in
transgenic mice [19]. High levels of mutated a-synuc-
lein expression under the mouse prion protein pro-
moter induced, for example, a progressive phenotype
with intraneuronal inclusions, degeneration and mito-
chondrial DNA damage in the neurons [20]. Although
no PD key symptoms were detected, this model is
valuable for understanding the relationship of a-synuc-
lein-positive protein depositions and neuronal damage.
Data from mouse models with mutant or wild-type
LRRK2 overexpression or null mutation have not yet
been published.
None of the genetic models based on PD-linked
genes recapitulate the key symptoms of the disease,
such as loss of dopamine neurons, but more subtle
effects on the DA system have been detected, such as a
small decrease in DAT binding and slightly reduced
DA levels in the striatum, abnormal response to DA
agonists, including apomorphine and amphetamine,
and motor disturbances, including decreased spontane-
ous activity together with protein-handling defects [17].
In several genetic models the MPTP-induced toxicity
for dopamine neurons has been analyzed and found to
Animal models of Parkinson’s disease M. Terzioglu and D. Galter
1386 FEBS Journal 275 (2008) 1384–1391 ª 2008 The Authors Journal compilation ª 2008 FEBS
be modified: a-Synuclein knockout mice were reported
to be less sensitive to MPTP, whereas a-Synuclein
transgenic mice and Dj-1 knockout mice were reported
to be more susceptible to the toxin [21]. Studies of the

KO) have adult onset of PD-like features [24]. During
the first 3 months after birth, the number of dopamine
neurons in the SN declined by about 70%, and DA
levels in the striatum were reduced by 40%, but the
degeneration abated at this level for the next
15 months. The mice slowly developed reduced loco-
motor activity and other motor deficits, but further
investigations are needed to clarify whether the altered
motor behavior is related to the loss of dopamine
neuron function or is caused by other cells deprived of
En, such as cerebellar neurons, a subset of interneu-
rons in the spinal cord or Bergman glia.
The aphakia mouse, a recessive phenotype that
occurred spontaneously, is characterized by small eyes
that lack a lens, caused by a deletion in the promoter
region of Pitx3. The gene expression of this homeobox
transcription factor is restricted to the developing eye
and to midbrain dopamine progenitor cells from
embryonic day 11 to adult life. Adult aphakia mice
develop SN-specific dopamine neuron loss combined
with a severe reduction of DA levels in the dorsolateral
striatum, whereas ventral tegmental area (VTA) dopa-
mine neurons are spared overall [25]. No intracellular
aggregations or LB-like inclusions have been detected.
The motor deficits include reduced rearing and sensori-
motor impairments, and repeated l-dopa treatment
induces dyskinesia in this genetic model [26].
Tissue-specific knockout mouse
models
Recently, a new type of rodent animal model for PD

rearing at different ages: at a few weeks for Dicer,at
several months for TFAM and at more than 1 year
for Ret conditional knockout mice. In MitoPark mice,
which have respiratory chain-deficient dopamine neu-
rons due to cell-specific ablation of TFAM, the motor
impairments are ameliorated by l-dopa administra-
tion, a common treatment for PD patients. Moreover,
MitoPark mice respond differently to the same dose
of l-dopa, depending on the progression of the symp-
toms, very similar to PD patients: in younger mice, as
in less severe PD patients, l-dopa treatment results in
a greater locomotor response than in older mice and
M. Terzioglu and D. Galter Animal models of Parkinson’s disease
FEBS Journal 275 (2008) 1384–1391 ª 2008 The Authors Journal compilation ª 2008 FEBS 1387
Table 1. Summary of advantages and disadvantages of selected rodent models of PD. Scoring of dopamine neuron: slight loss (< 30%);
loss (30–70%); massive loss (< 70%). The construct validity of a model refers to the degree to which the rodent model reproduces known
PD etiology (low = no findings in PD patients indicate a role in PD etiology for the toxin or genetic modification that the model is based on;
poor = some findings point to a role in PD etiology; good = findings in PD patients indicate a causative role for genetic modifications repro-
duced in the model). KO, knockout.
Model PD symptoms PD pathology Advantages Disadvantages
6-OHDA Motor impairments
after bilateral lesion
Easily quantifiable
turning behavior
after unilateral
lesion
Reduced DA levels in the
striatum
Massive loss of
dopamine neurons

(dangerous to
administer)
Reduced reliability
Paraquat Motor
impairments
Reduced DA levels
in the striatum
Loss of dopamine
neurons in the SN
No aggregate formation
Systemic administration Toxic for the whole
organism
Not well characterized
Low construct validity
Rotenone Motor
impairments
Reduced DA levels in the
striatum
Massive loss of
dopamine neurons
No aggregate formation
Systemic administration
Works only in rats
Toxic for the
whole organism
Low construct validity
Dj-1 KO, Pink1 KO,
Parkin KO
Little motor
impairment

impairment
Reduced DA levels in
the striatum
Massive loss of
dopamine neurons
in the SN only
Slow neurodegeneration Poor construct validity
Other cell groups
affected in the central
nervous system
MitoPark (DAT-cre,
Tfam lox ⁄ lox)
Motor
impairment
Reduced DA levels
in the striatum
Massive loss of
dopamine neurons,
predominantly in the
SN
Intracellular aggregates
with little LB
resemblance
Adult onset of
symptoms
Slow symptom
development
Good construct validity
Complex breeding
scheme

MitoPark mice display an additional pathological
hallmark of PD: affected dopamine neurons contain
cytoplasmic proteinaceous aggregates. However, unlike
LBs, these intracellular inclusions lack a-synuclein
immunoreactivity and they can also form in MitoPark
mice with a null mutation for a-synuclein, which
develop a progressive PD-like phenotype similar to
that seen in MitoPark mice with functional a-synuclein
genes. All other conditional mouse models for PD
described so far lack cytoplasmic inclusion bodies.
Conclusions
Regardless of whether a PD model is based on toxins
or on genome modifications, no single rodent model for
PD created to date reproduces all key symptoms of the
disease: slowly progressing motor disturbances com-
bined with loss of striatal dopamine fibers, and dopami-
ne cell loss in the SN accompanied by LB pathology.
Although toxin-induced models, particularly those
using drugs with a high specificity for dopamine
neurons, induce many of the key features of PD, they
are of lesser value in studies addressing PD etiology,
because only a few PD cases are caused by intoxication
with poisons (see also summary in Table 1). On the
other hand, genetic models based on genomic modifica-
tions found in PD patients have good construct validity
but show only rudimentary PD pathology. Those trans-
genic mouse models for a-synuclein exhibiting a more
pronounced PD phenotype have often used heterolo-
gous promoters (PDGFb, Thy1) that induce nonphysi-
ological high expression levels in restricted areas of the

(preclinical model)
Low construct validity
Complex breeding
scheme
DAT-cre,
Dicer lox ⁄ lox
Motor
impairment
Massive loss of TH-IR fibers
in the striatum
Massive loss of
dopamine neurons in
the SN and VTA
No aggregate formation
Possibility of studying
the role of
post-transcriptional
mechanisms in PD
Fast and early onset of
degeneration
Complex breeding
scheme
Low construct validity
M. Terzioglu and D. Galter Animal models of Parkinson’s disease
FEBS Journal 275 (2008) 1384–1391 ª 2008 The Authors Journal compilation ª 2008 FEBS 1389
MPTP); (b) high reliability, due to complete penetra-
tion and minimal variability; and (c) depending on the
floxed gene, the time course of the development of
neuropathology varies, but in all models there is slow
and progressive neurodegeneration, in contrast to the

(for MitoPark mice, about 5 months, and for DAT-
Ret
lox ⁄ lox
mice, more than 12 months), and because of
complex breeding schemes (only 25% of the offspring
in a litter have the affected genotype).
In conclusion, several recently generated rodent
models of PD reproduce more accurately the time
course of key symptoms and neuropathology develop-
ment seen in patients and are expected to further our
understanding of PD etiologies and help in the devel-
opment of new therapeutic strategies. Nevertheless, is
it important to keep in mind that several other neuro-
nal systems are affected in PD, changes that are not
reproduced in these disease models.
Acknowledgements
This work was supported by The Swedish Research
Council, The Swedish Brain Foundation, Swedish
Brain Power, the Swedish Parkinson Foundation and
Karolinska Institutet Funds.
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