Classic and new animal models of Parkinson's disease.
ABSTRACT Neurological disorders can be modeled in animals so as to recreate specific pathogenic events and behavioral outcomes. Parkinson's Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations.
- Journal of Neuropathology and Experimental Neurology 04/1996; 55(3):259-72. · 4.35 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.Neuron 10/2003; 39(6):889-909. · 15.77 Impact Factor
- Pharmacological Reviews 07/1959; 11(2, Part 2):490-3. · 22.35 Impact Factor
Hindawi Publishing Corporation
Journal of Biomedicine and Biotechnology
Volume 2012, Article ID 845618, 10 pages
Classicand NewAnimalModels of Parkinson’s Disease
1Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
2Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA
3Department of Neurology, Columbia University, New York, NY 10032, USA
Correspondence should be addressed to Serge Przedborski, SP30@Columbia.edu
Received 9 January 2012; Accepted 23 January 2012
Academic Editor: Monica Fedele
Copyright © 2012 Javier Blesa et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several
significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two
decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and
molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic
and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative
strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer
models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths
and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-
hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic
models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations.
Parkinson’s disease (PD) is the second most common neu-
rodegenerative disease, affecting 1% of the population over
55 years of age . This disease is characterized by the loss
of ∼50–70% of the dopaminergic neurons in the substantia
nigra pars compacta (SNc), a profound loss of dopamine
(DA) in the striatum, and the presence of intracytoplasmic
inclusions called Lewy bodies (LB), which are composed
mainly of α-synuclein and ubiquitin. Although mutations
in the α-synuclein gene have thus far been associated only
with rare familial cases of PD, α-synuclein is found in all
LBs . Therefore, this protein may play an important role
in the pathogenesis of this disease. The main features of PD
are tremor, rigidity, bradykinesia, and postural instability;
however, these motor manifestations can be accompanied by
nonmotor symptoms such as olfactory deficits, sleep impair-
ments, and neuropsychiatric disorders [3–5]. Although the
complete PD disease process is not yet understood, we have
gained a better understanding of its etiology, pathology, and
For example, reserpine administration in animals was found
to produce a profound depletion of monoamines, including
DA, in the brains of injected animals resulting in reserpine
syndrome. The symptoms of this syndrome consisted of
slowness of movement and rigidity  now commonly
associated with PD. Interestingly, it was found that L-DOPA
was able to reverse many of the symptoms associated with
reserpine administration , furthering the hypothesis that
DA depletion was at the root of PD symptomatology.
For the past several decades, animal models of PD have
come in a variety of forms. Typically, they can be divided
into those using environmental or synthetic neurotoxins or
reversible (reserpine) and irreversible (MPTP, 6-OHDA,
paraquat, rotenone) effects have been used effectively; how-
ever recent studies have focused more on irreversible toxins
to produce PD-related pathology and symptomatology.
those that produce an irreversible effect. Neurotoxin-based
2Journal of Biomedicine and Biotechnology
models produced by 6-hydroxydopamine (6-OHDA) and 1-
methyl-1,2,3,6-tetrahydropyridine (MPTP) administration
are the most widely used toxic models, while paraquat
and rotenone are more recent additions to the stable of
toxic agents used to model PD [6, 9]. A common feature
of all toxin-induced models is their ability to produce an
oxidative stress and to cause cell death in DA neuronal
populations that reflect what is seen in PD. Oxidative stress
results from increased production of extremely reactive free
radicals, including reactive oxidative species (ROS) and per-
oxynitrite. ROS may be formed during a number of cellular
processes, including mitochondrial oxidative respiration and
metabolism. There are some drawbacks to the use of these
models such as the time factor in these models versus the
time factor in the human condition, but these do not negate
the value of neurotoxin-based animal models in the study of
Recently, the identification of different genetic mutations
(α-synuclein, parkin, LRKK2, PINK1, DJ-1) has led to the
development of genetic models of PD . It is important
to remember that, at best, only ∼10% of PD cases are due
to genetic mutations , while the vast majority of PD cases
arise as sporadic, that is, from unknown origins. Although
the above-mentioned genes are mutated in PD and are not
overexpressed or knocked out, nonetheless, these animal
models are important in that they may reveal specific molec-
ular events that lead to the death of the DA neurons and
potential therapeutic targets. In this paper, we try to describe
the advantages and disadvantages of all of these animal
models and their potential roles in revealing the mechanisms
2.1. 6-Hydroxydopamine. 6-OHDA is the classic and oft
utilized toxin-based animal model of PD [11–13]. A lot of
information on the behavioral, biochemical, and physiologi-
model. 6-OHDA was first isolated in the 1950s . Unger-
dopaminergic pathway in the rat nearly 50 years ago, and the
use of 6-OHDA remains widespread today for both in vitro
and in vivo investigations. Mice, cats, dogs, and monkeys
are all sensitive to 6-OHDA; however it is used much more
frequently in rats [16–19]. Even though 6-OHDA exhibits
a high affinity for several catecholaminergic transporters
transporter (NET) , it is often used in conjunction
with a selective noradrenaline reuptake inhibitor such as
desipramine in order to spare the noradrenergic neurons
from damage in animal models of PD .
Although the structure of 6-OHDA is similar to that
of dopamine, the presence of an additional hydroxyl group
makes it toxic to dopaminergic neurons. This compound
does not cross the blood-brain barrier, which necessitates
its direct injection into the SNpc, medial forebrain bundle
(MFB), or the striatum [22, 23]. It is well known that 6-
OHDA destroys catecholaminergic neurons by a combined
Figure 1: Photomicrograph of a 6-OHDA lesioned rat striatum
immunostained for tyrosine hydroxylase (TH). Densities of TH-
immunoreactivity striatal fibers are clearly reduced after the 6-
OHDA injection (right side) as compared to the densities of striatal
TH-immunoreactivity fibers in control rat (left side).
effect of ROS and quinones , and it can induce inflam-
mation in the brain which tends to wane over time. The
most common use of 6-OHDA is via unilateral injection
into the rat medial forebrain bundle. Injection of 6-OHDA
into the SNpc kills approximately 60% of the tyrosine
hydroxylase- (TH-) containing neurons in this area of the
rodent brain with subsequent loss of TH-positive terminals
in the striatum  (Figure 1). Several studies have injected
this compound directly into the striatum in order to test
the hypothesis of retrograde degeneration, explicitly, that
TH-positive terminals in the striatum die prior to TH-
positive neurons in the SNpc, seemingly a replicate of PD in
humans [23, 26, 27]. The magnitude of the lesion depends
on the amount of 6-OHDA injected, the site of injection,
and the animal species used. This model does not mimic all
of the clinical features of PD. Dopamine depletion, nigral
dopamine cell loss, and neurobehavioral deficits have been
successfully achieved using this model, but it does not seem
to affect other brain regions, such as olfactory structures,
lower brain stem areas, or locus coeruleus. Although 6-
OHDA does not produce or induce proteinaceous aggregates
or Lewy-like inclusions like those seen in PD, it has been
reported that 6-OHDA does interact with α-synuclein .
6-OHDA is frequently used as a unilateral model because
the bilateral injection of this compound into the striatum
produces severe adipsia, aphagia, and also death [28, 29]
due to the animal’s inability to care for itself. One of the
most attractive features of the unilateral 6-OHDA model
is the fact that each animal can serve as its own control
as there is a lesioned and an unlesioned hemisphere. This
is particularly useful in behavioral analyses  as turning
behavior to amphetamine or apomorphine following the
unilateral application of 6-OHDA gauges the extent of the
induced SNpc or striatal lesion and the efficacy of potential
PD therapeutic agents and gene therapies [11, 30].
6-OHDA is an attractive candidate as a possible endoge-
nous toxin for the initiation of the PD neurodegenerative
process as it is a product of dopamine metabolism , and
it is the result of hydroxyl radical attack with the presence of
Journal of Biomedicine and Biotechnology3
Uses of the modelDisadvantages
Loss of DA innervation
at injection site
that may improve
of cell death
injection, very little
Loss of DA neurons
dependent on dosing
regimen, reaching 95%
in acute high-dose
Reduced DA levels in
with midbrain DA
Loss of DA neurons
accompanied by reduced
DA innervation in
Inclusions not prevalent.
Few cases of synuclein
nonhuman primates, as
well as increased
that may improve
of cell death
model of cell death.
Inclusiones are rare.
Synuclein aggregation in
and mortality. Labor
and time intensive.
No clear motor
Decreased striatal TH
No inclusions present,
but increased synuclein
immunoreactivity in DA
neurons of the SN
Not extensively tested.
Effects in other
deficits in the
less in the A30P
Generally no DA neuron
found in DA neurons,
generally restricted to
Study the role of
aggregation in PD,
as well as the
normal role of
Generally no DA
deficits seen in
No effect on DA
levels of degeneration in
Generally not observed
Study the role of
related to PD
General lack of
general lack of
excess dopamine; as a neurotoxin, it does produce lesions in
the nigrostriatal DA pathway. However, although it has been
measured in the brains of levodopa-treated rats subjected to
MPTP treatment, 6-OHDA has yet to be recovered from the
PD brain. Despite its limitations, this model has contributed
will continue to afford PD researchers a useful animal model
for PD research for long time.
2.2. MPTP. In 1982, MPTP was accidentally discovered in a
synthesis process gone awry, and, although it may have
caused some mayhem in certain circles, today it represents
the most important and most frequently used parkinsonian
toxin applied in animal models. Young drug addicts devel-
oped an idiopathic parkinsonian syndrome after intravenous
injection of this compound. After investigating the etiology
of their condition, it was found that MPTP was the neu-
rotoxic contaminant responsible for the parkinsonian effect
have consistently been pointed to as hallmarks of PD. It
has been repeatedly demonstrated that MPTP is indeed the
gold standard for toxin-based animal models of PD among
PD researchers for replicating almost all of these hallmarks
. Unfortunately, lacking in this list is the definitive
characteristic of PD, LB formation [33, 34]. Interestingly,
some studies have demonstrated the production of Lewy
body-like inclusions after MPTP administration [35, 36]
although these studies have been difficult to replicate. These
studies suggest that, under the right circumstances, we may
be able to reproduce the majority of hallmarks found in PD.
MPTP is highly lipophilic and after systemic admin-
istration rapidly crosses the blood-brain barrier. Once in
the brain, MPTP enters astrocytes and is metabolized into
MPP+, its active metabolite, by monoamine oxidase-B
(MAO-B). Recent findings show that once released from
the astrocytes into the extracellular space via the OCT-3
4Journal of Biomedicine and Biotechnology
Figure 2: Photomicrographs of nonhuman primate immunos-
tained for tyrosine hydroxylase (TH). Dopaminergic neurons
located in the substantia nigra compacta (SNc) project to the
caudate (CD) and putamen (PUT). Note the markedly reduced TH
immunoreactivity in the substantia nigra and striatum (CD and
PUT) in the MPTP-treated monkey (b) compared to control (a).
transporter , MPP+ is taken up into the neuron by the
uptake by the vesicular monoamine transporter (VMAT2)
. Consequently, mice lacking the DAT are protected from
MPTP toxicity . Once inside the neuron, MPP+ is able
to inhibit complex 1 of the mitochondrial electron transport
chain, resulting in the release of ROS as well as reduced ATP
production. Storing into vesicles can decrease MPP+ toxicity
[40–42]. Additionally, MPP+ stored in vesicles is thought
to expel DA out into the intercellular space where it can be
metabolized into a number of compounds, including toxic
metabolites, such as DOPAL and where it is can be subjected
to superoxide radical (5-cysteinyl-DA) and hydroxyl radical
(6-OHDA) attack [43, 44].
MPTP is used mainly in nonhuman primates and mice
cats . For unknown reasons, rats are resistant to MPTP
and mouse strains vary widely in their sensitivity to the toxin
. MPTP can be administered by a variety of regimens,
butthemost commonand reproducibleformis stillsystemic
injection (subcutaneous, intravenous) . When MPTP is
and neuroanatomical similarities to the human condition
showing a bilateral parkinsonian syndrome  (Figure 2).
Another commonly used route is the unilateral intracarotid
injection. This causes mostly a unilateral parkinsonism,
is technically more complicated to perform .
have introduced lower doses of the neurotoxin for longer
periods of time (subacute to chronic) to replicate more
closely the human pathology . There are recent studies
attempting to develop a more progressive model of PD.
In addition, models are being developed to study com-
pensatory mechanisms or recovery. These models use low
to intermittent doses administered once or twice per week
[51–54]. It is well known that monkeys exhibit variability
in MPTP susceptibility and that older primates are often
more susceptible to MPTP . MPTP-treated monkeys
respond well to antiparkinsonian treatments like L-DOPA or
develop dyskinesias. Recently, some studies have been taken
in order to study and evaluate the nonmotor symptoms
of the disease using this model [56–61]. This model has
also been used for electrophysiological studies, leading to
important findings, including the emergence of deep brain
stimulation, which is currently the best surgical method to
ameliorate symptoms in PD patients [62, 63].
Currently, the MPTP model is used more in mice than
in monkeys. Aside from the obvious financial benefits, the
mouse model is employed to test theories about cell death in
PD, to work out events in the neuronal death process, and
to study other pathological effects of PD. It is also extremely
useful as an initial screening tool to test potential treatments
for PD. On the other hand, the MPTP monkey model is
mainly used to discern behavioral and symptomatic compo-
nents of PD, as mice do not develop a level of impairment
equal to the human condition. Monkeys also represent the
last level of PD treatment research prior to any treatment
being administered to humans . However, the data
of molecular mechanisms involved in PD, and its utility
has proven invaluable. One of the most important aspects
of the MPTP mouse model is the possibility to work with
genetically modified mice [65, 66]. This model can be useful
for testing neuroprotective therapies. Currently, MPTP is the
standard bearer for toxin-based PD animal models.
3.1. Paraquat. Paraquat (N,N?-dimethyl-4-4-4?-bypiridini-
um) (PQ) is a herbicide widely used in agriculture that ex-
structural similarity, it was reasoned that PQ should behave
like MPP+. Epidemiological reports suggest that pesticide
there have been only 95 cases of PD linked to its toxicity in
humans . PQ exerts its deleterious effects through oxida-
tive stress mediated by redox cycling, which generates ROS.
In particular, the superoxide radical, hydrogen peroxide, and
hydroxyl radicals lead to the damage of lipids, proteins, DNA
and RNA [68, 69]. Recent evidence on the effects of PQ in
the nigrostriatal DA system is somewhat ambiguous as some
researchers report that, following the systemic application
of this herbicide to mice, animals exhibit reduced motor
activity and a dose-dependent loss of striatal TH-positive
striatal fibers and midbrain SNpc neurons [70, 71]. Other
researchers claim that no PQ-induced changes occur in the
nigrostriatal DA system [72, 73]. However, in a newer recent
study, Rappold et al.  demonstrate that PQ, in high
doses, employs the organic cationic transporter-3 (OCT-
3) and the dopamine transporter (DAT) and is toxic to
the DA neurons in the SN. Furthermore, they suggest that
the damage done by PQ is caused by radicalized PQ and
Journal of Biomedicine and Biotechnology5
facilitated by the glial cells. This means that PQ behaves
like MPP+ in exerting its toxic effects. Although this study
increases our understanding of how PQ may work, it does
not end the controversy about PQ and PD.
PQ’s importance to PD researchers is its ability to induce
increases in α-synuclein in individual DA neurons in the
SNpc and its ability to induce LB-like structures in DA neu-
rons of the SNpc . The relation of dopaminergic neuron
loss with α-synuclein upregulation and aggregation suggests
that this model could be valuable for capturing a PD-like
pathology. However, the molecular link between oxidative
stress and cell death in this model is still unknown. Thus, the
of the process of LB formation in DA neurons as well as the
tural chemicals known to cause damage to the dopaminergic
system. Maneb (manganese ethylenebisdithiocarbamate) has
been shown to decrease locomotor activity and potentiate
both the MPTP and the PQ effects [73, 76, 77]. Moreover,
the combination of PQ and maneb produced greater effects
on the dopaminergic system than either of these chemicals
alone. These compounds give credence to the theory that
environmental pesticides can cause PD [67, 78–80]. In fact,
recent studies have demonstrated that those exposed to
PQ or fungicides like maneb or ziram experience a greater
risk of developing PD [81, 82]. Further investigations using
these models are needed to determine the involvement of
environmental exposures in the etiology of PD.
3.2. Rotenone. Unlike PQ, which is a pure herbicide roten-
one, is both a herbicide and an insecticide . It is the most
potent member of the rotenoid family of neurotoxins found
naturally in tropical plants. The half-life of rotenone is 3–5
days depending on its exposure to sunlight, and it is rapidly
broken down in soil and in water . For these reasons,
rotenone is not considered to be a groundwater pollutant.
Rotenone is highly lipophilic and readily crosses the blood-
brain barrier. Chronic exposure to low doses of rotenone
results in inhibition of the mitochondrial electron transport
chain in the rat brain. In animals, rotenone has been admin-
istered by different routes. Oral administration appears
to cause little neurotoxicity [84, 85]. Chronic systemic
administration using osmotic pumps has been the most
common delivery regimen, especially in the Lewis rat, which
may be more sensitive to rotenone than other strains of
rats . Intraperitoneal injections have been reported
to elicit behavioral and neurochemical deficits, although
mortality is very high . Intravenous administration is
able to cause damage to nigrostriatal DA neurons that is
accompanied by α-synuclein aggregation, Lewy-like body
formation, oxidative stress, and gastrointestinal problems
it seems to replicate almost all of the hallmarks of PD
including causing α-synuclein aggregation and Lewy-like
body formation [89, 90]. Interestingly, a subsequent study
has found that rotenone is not specific to the DA system
and has deleterious effects on other neuronal populations.
Likewise, in PD in which neurodegeneration extends beyond
the dopaminergic system, rotenone is associated with 35%
reduction in serotonin, 26% in noradrenergic, and 29%
in cholinergic neurons . However, when rotenone was
administered chronically at lower doses to achieve complex
I inhibition similar to that observed in patients, it seems
to produce a highly selective nigrostriatal degeneration 
although only about 50% of the treated rats exhibit nigros-
triatallesions. Thecontroversyaboutthe useof rotenone asa
model of PD is that although it does augment DA oxidation,
evidence is slim on depletion of DA in the nigrostriatal
system . Attempts to lesion other animal species such
as mice or monkeys have not been successful at all [72, 92].
However, recent studies by two groups have demonstrated
that oral administration of rotenone to mice causes nigral
degeneration, a decrease of striatal dopamine levels, and
motor dysfunction [85, 93, 94]. They also demonstrated α-
synuclein aggregation in different areas of the brain .
Furthermore, there are no documented cases of rotenone-
induced PD in humans. Thus, it is not clear that this model
offers any advantage over other toxic models, such as that of
6-OHDA or MPTP.
The underlying principle for studying genetic mutations of
a disease is the belief that the clinical similarities between
the inherited and sporadic forms of the disease share a
common mechanism that can lead to the identification of
molecular and biochemical pathways involved in the disease
only about 10% of all PD cases . And animal models
of these mutations (α-synuclein and LRRK2, autosomal
dominant PD) and (PINK1/Parkin and DJ-1, autosomal
recessive PD) are important as they represent potential
therapeutic targets. However, we must first understand the
workings of these animal models because it is becoming
clearer that there are many facets to PD disease.
Mutations to the α-synuclein gene, which is normally
thought to play a role in the synaptic vesicle recycling,
were the earliest evidence for genetic link to PD. Two
mutations in the α-synuclein gene (A53T, A30P) cause
a dominantly inherited form of PD  and have been
used to create transgenic mice in an effort to recapitulate
the pathophysiology of PD. Studies done using α-synuclein
transgenic mice have yielded considerable progress, showing
that A53T mutations in mice can result in a severe motor
phenotype which can eventually lead to paralysis and death
. Additionally, mutations to the α-synuclein gene in mice
produce inclusions that resemble LBs . However this
phenotype is generally restricted to the A53T mutation and
not found in A30P transgenic mice. Indeed, it has been
shown that knocking out α-synuclein does not affect DA
neuron development or maintenance [99, 100] suggesting
that the loss of α-synuclein probably plays no role in the
degeneration of DA neurons that is seen in PD. Interestingly,
studies done in Drosophila expressing mutant α-synuclein
show dopaminergic cell loss, reduced TH expression in
the SN, filamentous intraneuronal inclusions, and motor
deficits . Some of the α-synuclein transgenic mice have
olfactory impairments and colonic dysfunction, and it seems
6Journal of Biomedicine and Biotechnology
that there are other nonmotor abnormalities . Under-
standing these nonmotor symptoms could offer new model
for testing therapies focused on the nonmotor symptoms.
However, since the function of α-synuclein has yet to be
figured out, the actual role of α-synuclein in PD still remains
Mutations to the LRRK2 gene have been shown to cause
a dominant form of PD . Unlike α-synuclein which is
ubiquitous, LRRK2 (leucine rich repeat kinase 2) is localized
to membranes. However, similar to α-synuclein transgenic
mice, it has been determined that knocking out LRRK2
has no effect on DA neuron development and maintenance
. Moreover, Drosophila models are limited in their
translation to the human condition, and the LRRK2 mouse
model is not particularly a strong model as it shows only
minimal levels of neurodegeneration .
Mutations to parkin (which accounts for about 50%
of the familial cases of PD and 20% of the young onset
PD cases), DJ1 (a redox sensitive molecular chaperone and
regulator of antioxidant gene expression), and PINK1 (phos-
which is localized to the mitochondrial intermembrane
space) cause autosomal recessive forms of PD. Knock-out
triatal degeneration, present with intranucelar inclusions,
or displays any form of DA neuron loss that resembles
idiopathic or inherited PD and fail to develope any type of
behavioral or pathological phenotype (only PINK1 knock-
out mice display reduced DA release in the striatum) .
However, recently it has been shown that knocking out
parkin in mice at adult age causes neurodegeneration in the
Overall, this genetic mouse models are able to recapit-
ulate specific aspects of PD, although none produce the
neuronal degeneration associated with PD; therefore these
themselves may be defective and may require additional
modulations or modifications, like for example the human
Animal model systems are the closest to humans that we
are able to study. A number of animal models of PD have
been developed to understand the pathogenesis and test
potential therapeutics of this disease. In this paper we have
summarized the most prominent aspects characterizing the
most popular toxic and genetic models of PD. Each model
has advantages and disadvantages as we have discussed in
this paper. Toxic models offer some of the hallmarks of
PD while genetic models offer others. Meanwhile the toxic
models are useful to screen drugs for symptomatic treatment
of the disease; transgenic or knockout models are useful for
evaluating the role of genetics in PD. The drawback of the
toxin models is that most of them resemble PD at late stages,
whereas genetic animal models use either overexpression or
knock-out technology to model disease from early on. The
choice of the model to be used depends on the questions
being asked. With toxin models, we are working toward
developing a progressive model by tempering the toxic doses
right balance of contributing components through knock-in
or conditional technology. However, there is much progress
to be made, because it seems unlikely that a single model,
be it toxic or genetic, can fully recapitulate the complexity of
human PD. Future models should involve a combination of
neurotoxin-induced and genetically induced models ideally
taking into account factors of aging and environmental
The authors are supported by grants from the National
Institutes of Health (NS042269, NS064191, NS38370,
NS070276, and NS072182), the US Department of
Defense (W81XWH-08-1-0522, W81XWH-08-1-0465, and
W81XWH-09-1-0245), the Parkinson Disease Foundation,
the Thomas Hartman Foundation For Parkinson’s Research,
Project A.L.S, the Muscular Dystrophy Association/Wings
over Wall Street. J. Blesa is supported by a fellowship from
the Spanish Ministry of Education.
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