This 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 mode
Trang 1Parkinson’s disease: genetic versus toxin-induced rodent models
Mu¨gen Terzioglu1and Dagmar Galter2
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;
intracellular aggregates; mitochondrial
dysfunction; MPTP; PARK genes;
progressive neurodegeneration; a-synuclein
Correspondence
D Galter, Department of Neuroscience,
Karolinska Institutet, Retzius va¨g 8,
171 77 Stockholm, Sweden
Fax: +46 8 32 37 42
Tel: +46 8 524 87018
E-mail: dagmar.galter@ki.se
(Received 23 October 2007, revised 17
December 2007, accepted 7 January 2008)
doi:10.1111/j.1742-4658.2008.06302.x
Parkinson’s disease (PD), a common progressive neurodegenerative disor-der, is characterized by degeneration of dopamine neurons in the substantia nigra and neuronal proteinaceous aggregates called Lewy bodies (LBs) The etiology of PD is probably a combination of environmental and genetic factors Recent progress in molecular genetics has identified several genes causing PD, including a-synuclein, leucine-rich repeat kinase 2 (LRRK2), Parkin, DJ-1 and PTEN-induced kinase 1 (PINK1), many of them coding for proteins found in LBs and⁄ or implicated in mitochondrial function However, the mechanism(s) leading to the development of the disease have not been identified, despite intensive research Animal models help us to obtain insights into the mechanisms of several symptoms of PD, allowing us to investigate new therapeutic strategies and, in addition, pro-vide an indispensable tool for basic research As PD does not arise sponta-neously in animals, characteristic and specific functional changes have to
be induced by administration of toxins or by genetic manipulations This 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.
Trang 2putamen 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 slowarrest-ing 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
together with specific behavior tests to assess motor
dysfunctions
This review focuses on rodent animal models and
compares the most recently available tissue-specific
knockout mouse models with older genetic and
toxin-induced animal models (Fig 1)
Toxin-induced animal models
Early animal models developed for PD research used
neurotoxins specific for the dopamine (DA) system
such as 6-hydroxydopamine (6-OHDA) and
1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) For a
recent review on classic toxin-induced animal models,
see also Schober [1]
The hydroxylated derivative of the neurotransmitter
DA was first used in sympathetic heart denervation,
and soon after in the central nervous system [2] When
the drug is stereotactically injected into the striatum, the median forebrain bundle or the SN, it induces fast and irreversible DA depletion through reactive oxygen species (ROS) formation and toxic quinines [3] The relative specific toxicity of 6-OHDA for catecholamine neurons results from its uptake by DA and noradrena-lin transporters Most widely used is the unilateral lesion of the DA system in rats, where a quantifiable circling behavior is induced after injection of DA receptor agonists or amphetamine In addition, several other behavioral assessments, such as fine motor skill tasks and the cylinder test, have been developed to measure striatal DA loss [4] Furthermore, rodent ani-mal models for dyskinesia are mostly based on unilat-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
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 affected where the genes are active Protein aggregations, altered protein handling and mitochondrial deficits have been detected in these mouse models, mainly in the DA system (C) Dopamine neuron-specific knockout models: using DAT promoter driven cre expression, three mice models with targeted deletion of floxed genes have been generated to date: deleting the GDNF receptor Ret, the RNA-cleaving enzyme complex Dicer and TFAM from dopamine neurons.
Trang 3of the mitochondrial respiratory chain As the
suscepti-bility to MPTP depends on the MAO-B activity,
dif-ferent mouse strains react very difdif-ferently to the toxin
Rats are relatively resistant to MPTP, whereas humans
are in danger of intoxication at quite low doses In
mice, systemic MPTP treatment induces bradykinesia,
rigidity and posture abnormalities combined with a
depletion of dopamine neurons [8] Continuous MPTP
infusion by minipumps has been reported to induce
development of intracellular inclusion bodies [9],
although these inclusions are not similar to the LBs
typically found in human disease [10]
More recent toxin-induced animal models make use
of agents with a general toxicity: mitochondrial
func-tion inhibitors such as the herbicide paraquat and the
insecticide rotenone, or proteasomal inhibitors such as
epoxomicin
Paraquat is structurally similar to MPTP, but has
no selectivity for DAT and does not accumulate in
dopamine neurons after systemic administration
Nev-ertheless, it induces a specific, although modest, loss of
tyrosine hydroxylase (TH)-positive neurons of the SN
pars compacta [11,12] Rotenone, produced in the
roots and stems of tropical plants, inhibits the transfer
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+- or rotenone-induced
dopamine neuron death in rats and induced round
a-synuclein IR inclusions in dopamine neurons [16]
In summary, most toxins used in PD animal models inhibit mitochondrial function and reveal a greater susceptibility of dopamine neurons to mitochondrial dysfunction and ROS production
Genetically modified mouse models Although the majority of PD cases are sporadic, sev-eral mutations in genes causing familial forms of PD have been recently discovered, and many susceptibility genes have also been identified, leading to new approaches to the study of mechanisms leading to dis-ease Many animal models are based on genetically modified mice with null mutations, an extra gene copy,
or point mutations of genes located in different PARK loci [17,18]
For the recessively inherited loss-of-function muta-tions in Parkin, DJ-1 and PINK1, all of which cause early-onset PD, genetic mouse models can easily be made by null mutation of such genes (knockout mice) For the dominantly inherited gain-of-function muta-tions such as in a-Synuclein and leucine-rich repeat kinase 2 (LRRK2), transgenic mouse models have been created in which extra copies of the gene are intro-duced into the mouse genome or delivered by lenti- or adeno-associated virus Several mouse strains have been created for a-Synuclein, where either the human wild-type gene is overexpressed under various heterolo-gous promoters, to reproduce the gene duplication and 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
Trang 4be 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
effects of toxins in genetic PD models can provide
important clues, because the etiology and progression
of the disease can be due to a combination of genetic
factors and environmental exposures Moreover, many
genes implicated in PD are directly or indirectly
involved in mitochondrial function: PINK1, DJ-1 and
possibly Parkin and LRRK2 are at least partly
local-ized to mitochondria; in a-Synuclein transgenic mice,
mitochondrial pathology has been detected; in mice
lacking the mitochondrial protease HtrA2⁄ Omi, motor
impairment due to striatal cell loss has been reported
[22], and in PolG, the mitochondrial DNA polymerase,
genetic variants associated with PD have been
identi-fied [23] These genetic findings together strongly
sug-gest mitochondrial involvement in the etiology of PD
Detection of genes that are critical for the
develop-ment and survival of dopamine neurons has led to
additional mouse models, such as the spontaneously
occurring Pitx3-aphakia mouse or the Engrailed (En)
double-knockout mouse model
En1 and En2 homeobox transcription factors are
expressed as early as embryonic day 8, and they play a
role in the development of the midbrain and
cerebel-lum Later in development they have additional
func-tions, such as being survival factors for mesencephalic
dopamine neurons, where the two genes can
compen-sate for each other Heterozygous knockout mice of
En1and homozygous knockout of En2 (En1+⁄); En2
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 loco-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 has been established, using conditional knockout strat-egies in order to disrupt the expression of genes of interest in a region- or neuron-specific manner For this purpose, mice that express cre-recombinase (cre) under the control of the DAT promoter are predomi-nantly used to target postmitotic dopamine neurons in the midbrain [27–30] Other mouse strains targeting wider populations of neurons are also available: cre expression driven by the TH promoter targets all cate-cholamine neurons in the central and peripheral ner-vous system [31,32]; Mice in which cre expression is driven by the En1 promoter [33] or by wingless-1 [34] target the early stages of the developing DA system, although these mice are less convenient as PD models because neither transcription factor is exclusively expressed by dopamine neurons of the midbrain
To generate mice with specific deletion of a particu-lar gene, one of these cre-expressing mouse strains is bred with mice homozygous for a floxed gene; that is, both chromosomal copies of the gene are flanked by LoxP recombination sites
Examples of floxed genes used in conditional mouse models are: the mitochondrial transcription factor A (TFAM) [35], the microRNA enzyme Dicer [36], and the receptors for neurotrophic factors Ret [for glial-cell-line derived neurotrophic factor (GDNF)] and TrkB [for brain-derived neurotrophic factor (BDNF)] [37] Deletion of TFAM, Ret or Dicer in dopamine neurons induces progressive motor dysfunctions such
as slowness and pauperism of movements and limited 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
Trang 5Table 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.
after bilateral lesion Easily quantifiable turning behavior after unilateral lesion
Reduced DA levels in the striatum
Massive loss of dopamine neurons
No intracellular aggregates
Works in mice, rats, and monkeys
Well characterized Used in dyskinesia models
Does not pass the blood–brain- barrier (needs intracerebral injection, which increases variability) Fast, massive neurodegeneration Poor construct validity
impairments
Reduced DA levels in the striatum
Massive loss of dopamine neurons With chronic administration, formation of aggregates with little LB resemblance
Lipophilic Systemic administration Works mainly in mice Well characterized Good construct validity
Highly toxic to humans (dangerous to administer) Reduced reliability
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
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
Only slight DA pathology Good construct validity Slight DA pathology a-Synuclein wild-type
and A53T, A30P
overexpression
Little motor impairment
Little DA pathology Intracellular aggregates with little LB resemblance
Good construct validity Slight DA pathology
En1+⁄), En2 KO Some motor
impairment
Reduced DA levels in the striatum Massive loss of dopamine neurons only in the SN during the first 3 months
No aggregate formation
Slow neurodegeneration Poor construct validity
Other cell groups affected in the central nervous system
No progression of degeneration after
3 months
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
Trang 6PD patients with severe motor dysfunctions [35] In
parallel with behavioral changes in all three models,
the degeneration of dopamine nerve terminals in the
striatum and a progressive loss of dopamine neurons
specifically in the SN pars compacta occur In
con-trast, VTA neurons appear to be more resistant to
the ablation of TFAM and Ret, because the loss of
nerve terminals in the ventral striatum and cell loss in
VTA occur later and are less pronounced than in the
SN pars compacta, similar to the pathological
devel-opment in PD [35,37] Ablation of Dicer induces a
similar degree of degeneration in dopamine neurons
of the SN pars compacta and the VTA [36] The
dopamine cell loss results in reduced DA levels in the
corresponding parts of the nigrostriatal system in
middle-aged MitoPark mice together with a marked
increase of DA turnover, as is typically seen in PD
and animal models with DA deficiency [35] In
Ret-deficient mice, dopamine cell and nerve terminal
losses are less than 40%, even in 24-month-old mice,
and DA levels in the striatum are unaltered
How-ever, evoked DA release after electrical stimulation
reveals a significant drop in 1-year-old mice and a
further reduction in older mice, consistent with
pre-symptomatic development in PD patients Dopamine
neuron-specific ablation of TrkB, in contrast, did not
affect the motor behavior and nor did it induce any
PD-like neuropathology [37]
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 brain Interestingly, in some studies, genetic models are combined with PD-specific toxins to analyze the effect
of the genetic modification on toxin susceptibility The two genetic PD models based on ablation of the transcription factors En and Pitx3 display many of the key features of PD Their drawbacks are low construct validity, because few studies point to an involvement
of DA system development in PD etiology, and the fact that many different cell populations in the brain are affected in En or Pitx3 knockout mice as well as dopamine neurons, making it difficult to interpret the findings
Tissue-specific knockout models for PD based on cre expression directed by the DAT promoter combine the advantages of the earlier models: (a) only dopa-mine neurons are targeted like in toxin models with mainly DA-specific neurotoxicity (6-OHDA and
Table 1 (Continued).
DAT-cre,
Ret lox ⁄ lox
No motor impairment
Slight loss of dopamine neurons in the SN Slow loss of TH-IR fibers
No reduction in DA levels Reduced DA release
No aggregate formation
Very slow progression (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
Trang 7MPTP); (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
acute and violent degeneration seen, for instance, in
the 6-OHDA model Slow progressive dopamine
neu-ron degeneration has also been achieved through
chronic MPTP administration, albeit associated with
high morbidity due to drug toxicity The construct
validity of the models also varies with the floxed gene
To date, genetic studies have not indicated
distur-bances of neurotrophic factors or their receptors as
causes of PD, reducing the construct validity for the
DAT-Retlox⁄ loxmodel Dopamine neuron-specific
dele-tion of Dicer induces decreased expression of the
micr-oRNA miR133b, which reproduces a deficiency found
in midbrain tissue from PD patients and gives this
model good construct validity There are several
indi-cations that mitochondrial dysfunction plays a
promi-nent role in the etiology and progression of PD, both
from genetic studies (genetic variants of the mtDNA
polymerase PolG have been associated with PD, and
higher loads of mtDNA point mutations or deletions
have recently been found in dopamine neurons from
PD patients) and from toxin studies (dopamine
neu-rons are more susceptible than other neuneu-rons to
mito-chondrial toxins such as rotenone or paraquat than
other neurons), conferring good construct validity also
to the MitoPark model
What are the disadvantages of the tissue-specific
knockout models? There are high costs of animal care,
because of the slow development of the phenotype
(for MitoPark mice, about 5 months, and for
DAT-Retlox⁄ 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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