Abstract
Parkinson’s disease (PD) is a multifactorial disease with a complex etiology that results from genetic risk factors, environmental exposures and most likely a combination of both. Rodent models of parkinsonism aim to reproduce key pathogenic features of the syndrome including movement disorder induced by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the formation of α-synuclein containing Lewy body inclusions. Despite the creation of many excellent models, both chemically induced and genetically engineered, there is none that accurately demonstrates these features. Recent pathological staging studies in man have also emphasized the significant non-CNS component of PD that has yet to be tackled. Herein, we summarize rodent models of PD and what they offer to the field, and suggest future challenges and opportunities.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Parkinson’s disease (PD) affects 5% of the general population by the age of 85, whereas early-onset disease < 50 years is infrequent (Twelves et al. 2003). Clinically the condition is characterized by parkinsonism, the triad of motor features including resting tremor, bradykinesia and rigidity that present asymmetrically and progressively worsen. Pathologically, neuronal loss is observed for the pigmented, dopamine producing neurons of the substantia nigra whilst Lewy bodies containing aggregated α-synuclein are found in surviving cells of the brainstem. Initially, patients respond well to dopaminergic replacement therapy but treatment is effective for only a limited period and fails to halt disease progression. Neuroprotective interventions and the ability to measure their efficacy are required.
The etiology of PD is unknown; however, it has long been suggested that environmental factors may contribute. The first acute models were created using 6-hydroxydopamine (6-OH-DOPA) and provided fundamental insights into basal ganglia physiology, whereas mitochondrial complex I poisons such as 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) or rotenone, chronically administered at low dose, have provided more progressive models of disease. Proteosome inhibitors, such as epoxomicin, have been shown to recapitulate many of the central features of PD including motor impairment and neuropathology, but these effects have been difficult to reproduce (McNaught et al. 2004). Genetic mutations identified in familial parkinsonism have recently provided new tools to implicate and understand the molecular pathways affected. In the past decade, recessively inherited loss-of-function mutations in Parkin (PRKN), DJ-1 and PTEN-induced putative kinase-1 (PINK1) were found to cause early-onset (< 50 years at onset), l-DOPA-responsive parkinsonism. The slowly progressive and predominant motor phenotype in these patients suggests a disorder largely restricted to dopaminergic neuronal loss. PINK1 and DJ-1 cases have not yet to come to autopsy, but the majority of patients with Parkin-linked disease demonstrate neuronal loss restricted to the substantia nigra. In contrast, dominantly inherited, gain-of-function mutations in α-synuclein (SNCA) and leucine-rich repeat kinase (LRRK2) result in more typical, late-onset, Lewy body parkinsonism with multi-system involvement (reviewed by Ross and Farrer 2005).
The future of drug therapies for PD depends on developing animal models that recapitulate the disease and in which new compounds may show efficacy. Focusing primarily on rodent models we review progress to date and opportunities for future research.
Toxins and the environment
6-OH-DOPA
6-OH-DOPA administration causes nigrostriatal depletion when stereotaxically injected into the substantia nigra, median forebrain bundle or striatum. 6-OH-DOPA destroys catecholaminergic structures through a combination of reactive oxygen species and increased toxic quinones (reviewed by Bove et al. 2005). After injection in rats dopaminergic neurons die within 24 h, show apoptotic morphology (Jeon et al. 1995) and decreased α-synuclein mRNA (Kholodilov et al. 1999; Zeng et al. 2002) but Lewy body formation has not been demonstrated. Nevertheless, unilateral lesions result in an asymmetric circling behavior that has been used extensively to evaluate anti-parkinsonian therapeutics.
MPTP
MPTP was inadvertently used as a ‘street drug’ in the eighties and results in parkinsonism (Langston et al. 1983). MPTP is a potent and irreversible mitochondrial complex I inhibitor whose toxic metabolite MPP+ is selectively transported by the dopamine transporter DAT (Kopin and Markey 1988; Speciale 2002; Schober 2004; Watanabe et al. 2005). Although dopaminergic neurons in rats are relatively resistant to MPTP-induced toxicity (Bove et al. 2005), in mice susceptibility of the nigrostriatal pathway to neurodegeneration is strain-dependent with C57BL6 being more sensitive and Balb/c more resistant to MPTP-induced neurotoxicity (Sedelis et al. 2001). In humans acute intoxication with MPTP does not result in Lewy bodies (Langston et al. 1983), but in both rodents and primates α-synuclein expression is chronically upregulated after an acute dose (Vila et al. 2000; Purisai et al. 2005). Transgenic mice overexpressing wild type and mutant human α-synuclein have increased sensitivity to MPTP (Song et al. 2004; Nieto et al. 2005), whereas α-synuclein knock-out mice have reduced sensitivity, suggesting genetic and environmental causes may converge (Dauer et al. 2002; Schluter et al. 2003; Drolet et al. 2004; Robertson et al. 2004; Klivenyi et al. 2005).
Paraquat
The herbicide paraquat is structurally similar to MPP+ and is also a mitochondrial complex I inhibitor; however, it differs in its mechanism of action from MPP+ in that it is not a substrate or an inhibitor of the dopamine transporter, DAT (Richardson et al. 2005). When administered to mice paraquat also leads to upregulation and aggregation of α-synuclein (Manning-Bog et al. 2002). In addition, combined exposure to herbicide paraquat and the fungicide maneb leads to selective loss of dopamine and dopaminergic neurons in the substantia nigra of mice, an effect which is more pronounced postnatally than compared with administration in adults (Cory-Slechta et al. 2005).
Rotenone
Chronic administration of rotenone in rodents can produce a progressive model of parkinsonism associated with α-synuclein upregulation and accumulation in Lewy-like pathology (Betarbet et al. 2000; Sherer et al. 2002, 2003). In contrast to MPTP and paraquat, which accumulate selectively in dopaminergic neurons, chronic exposure to rotenone can produce mild but systemic complex I inhibition. When a degenerative lesion results it is selective to the nigrostriatal system, indicative of the vulnerability of this neuronal population to oxidative stress.
Epoxomicin
Systemic administration of the proteasomal inhibitor epoxomicin to adult rats has been shown to reproduce many key features of PD. In the original study, animals develop progressive parkinsonism with bradykinesia, rigidity, tremor, and an abnormal posture which improves with apomorphine treatment (McNaught et al. 2004). Using positron emission tomography, degeneration of the nigrostriatal pathway was indicated by reduction in carbon-11-labeled 2-beta-carbomethoxy-3-beta-(4-fluorophenyl) tropane binding to dopaminergic nerve terminals in the striatum. Postmortem analyses showed striatal dopamine depletion and dopaminergic cell death with apoptosis and inflammation in the substantia nigra. Additionally, intracytoplasmic, eosinophilic, α-synuclein/ubiquitin-containing inclusions resembling Lewy bodies were present in some of the remaining neurons (McNaught et al. 2004). This model promised to be one of the most successful in recapitulating the progressive movement disorder and pathology associated with PD but has since proven very difficult to reproduce.
Recessive genes implicated in parkinsonism
Parkin models
Homozygous and compound heterozygous Parkin mutations were originally identified in Japanese families with autosomal recessive, juvenile parkinsonism (Kitada et al. 1998). Point mutations, exonic rearrangements, deletions and duplications are common (reviewed by Mata et al. 2004). Through imaging studies carriers of heterozygous Parkin mutations have been associated with clinically asymptomatic deficits of dopaminergic function (Khan et al. 2002; 2005; Pramstaller et al. 2005). However, whether these individuals have increased susceptibility to late-onset PD remains unclear (West et al. 2002; Lincoln et al. 2003). Mutations in Parkin are thought to impair its E3 ubiquitin protein ligase activity and result in improper targeting of substrates for proteasomal degradation, and may lead to subsequent neurotoxic accumulation. A number of substrates have been reported including Parkin-associated endothelin-like receptor, a rare glygosylated form of α-synuclein and the p38 subunit of the aminoacyl-tRNA synthetase complex (reviewed by Moore et al. 2005).
Several groups have also described spontaneous and targeted knockout of the Parkin gene in mice (Goldberg et al. 2003; Itier et al. 2003; Lorenzetti et al. 2004; Von Coelln et al. 2004; Perez and Palmiter 2005). Homozygous Quaking mice lack both Parkin and Parkin co-regulated gene (PACRG), although their demyelination phenotype has long been attributed to the neighboring locus and dysregulation of quaking mRNA expression (Lockhart et al. 2004; Lorenzetti et al. 2004). Surprisingly, these mice have no evidence for dopaminergic cell loss (Lorenzetti et al. 2004). Targeted knock-out mice deficient in Parkin via deletion of exon 3 or 7 also have normal brain morphology and have normal numbers of dopaminergic neurons. However, subtle nigrostriatal deficits are apparent, including increased levels of extracellular dopamine (Goldberg et al. 2003; Itier et al. 2003; Von Coelln et al. 2004), reduction in synaptic excitability in the striatum (Goldberg et al. 2003) and altered energy metabolism, protein handling and synaptic function (Periquet et al. 2005). In contrast, homozygous mice lacking exon 2 of Parkin are indistinguishable from their wild-type littermates (Perez and Palmiter 2005). Administration of 6-OH-DOPA or metampthetamine did not reveal any increased sensitivity in this model (Perez et al. 2005). However, overexpression of Parkin mediated by adenoviral delivery does ameliorate α-synuclein-induced dopaminergic neuron loss and consequent motor dysfunction (Yamada et al. 2005).
DJ-1 models
Mutations in DJ-1, originally described in a Dutch kindred (Bonifati et al. 2003), are rare accounting for less than 1% of early-onset parkinsonism. DJ-1 is a member of the ThiJ/PfpI family of molecular chaperones which are induced during oxidative stress; the protein exists primarily as a dimer localized to mitochondria (Tao and Tong 2003; Zhang et al. 2005). Loss-of-function mutations are thought to cause PD via impaired oxidative stress protection. DJ-1 null mice with either exons 1–5 deleted or only exon 2 deleted display subtle behavioral deficits, increased striatal dopaminergic re-uptake rates and elevated dopamine levels (Chen et al. 2005; Goldberg et al. 2005). In mice with homozygous exon 2 deletion, long-term depression was found to be absent and was reversible by D2 but not D1 agonist treatment suggesting an essential role for D2-receptor mediated function. No changes in dopaminergic neuronal number were observed in either model. DJ-1 null mice treated with MPTP showed increased striatal denervation and dopaminergic neuron loss compared to wild-type mice, whereas DJ-1 adenoviral vector delivery mitigates this phenotype. Indeed, wild-type mice that receive adenoviral delivery of DJ-1 effectively resist MPTP induced striatal damage (Kim et al. 2005). Thus, in vivo data suggest loss of DJ-1 may lead to parkinsonism by conferring hypersensitivity to dopaminergic insults, whereas DJ-1 overexpression appears to protect against neuronal oxidative stress.
Dominant genes implicated in parkinsonism
α-synuclein models
SNCA encoding α-synuclein was the first gene to be linked to familial parkinsonism for which three missense and several multiplication (duplication and triplication) mutations have now been described (reviewed by Hope and Farrer 2004). Neither homolog β- nor γ-synuclein has been convincingly implicated in PD.
Knock-out mice
Several knock-out mice (KO) models have been created, all are viable and show subtle phenotypic effects (if any). Initial efforts to ablate SNCA exons 1 and 2 resulted in a modest decrease of striatal dopamine levels and attenuated locomotor activity in response to amphetamine (Abeliovich et al. 2000). In contrast, mice with disruption of SNCA exons 4 and 5 did not display changes in locomotor activity following amphetamine treatment. A reduction in the reserve pool of synaptic vesicles in the hippocampus was observed but striatal dopamine levels were not significantly decreased (Cabin et al. 2002). In another model disruption of SNCA exon 2 did not result in altered dopamine levels or dopamine uptake, although modest upregulation of β-synuclein was noted in the striatum (Schluter et al. 2003). In a subpopulation of C57BL/6J mice the SNCA locus was also discovered to be spontaneously deleted. Consistent with findings in targeted knockout models, the mice were phenotypically normal and there was no evidence of compensatory upregulation of β- or γ-synuclein proteins (Specht and Schoepfer 2001). Of note, double α- and β-synuclein knockouts have normal survival and brain function, showing only small compensatory increases in γ-synuclein, a subset of 14-3-3 proteins (involved in signaling and phospho-protein dimerization), and in complexin, which like synuclein is a small soluble pre-synaptic protein (Chandra et al. 2004). Overall, these findings suggest ablation of α- and β-synuclein family members has little impact on the development of the murine brain.
Mutant and wild-type over-expression α-synuclein models
Despite its seemingly superfluous role in mice, mutant and wild-type α-synuclein is clearly associated with PD in humans (reviewed by Hope and Farrer 2004). A variety of α-synuclein transgenic mouse models have now been described, most utilizing a cDNA construct with a heterologous promoter. Wild-type overexpression recapitulates many of the features of PD including mislocalization of α-synuclein from its normal axonal/synaptic location into neuronal cell bodies (Kahle et al. 2000; Masliah et al. 2001; Matsuoka et al. 2001; Richfield et al. 2002; Rockenstein et al. 2002), non-fibrillar and detergent insoluble accumulation of α-synuclein (van der Putten et al. 2000; Kahle et al. 2001; Masliah et al. 2001), reduced dopaminergic (tyrosine hydroxylase positive) nerve terminals in the striatum and motor abnormalities (Masliah et al. 2000; van der Putten et al. 2000; Masliah et al. 2001; Fleming et al. 2004).
Human A30P mutant α-synuclein mice also display mislocalization of α-synuclein (Kahle et al. 2000; Matsuoka et al. 2001; Lee et al. 2002; Gomez-Isla et al. 2003) but lack fibrillar inclusions, although detergent insoluble accumulation has been observed in one model (Kahle et al. 2001). In addition gliosis (Gomez-Isla et al. 2003), progressive motor abnormalities (Gomez-Isla et al. 2003), altered short-term hippocampal synaptic plasticity (Steidl et al. 2003), increased tau phosphorylation at Ser 396/404 and Ser 202 (Frasier et al. 2005) and motor dysfunction (Gomez-Isla et al. 2003) have all been described. Kahle and colleagues also showed that A30P α-synuclein was normally transported to synapses in contrast to in vitro data (Jensen et al. 1998; Kahle et al. 2001).
The human A53T α-synuclein mutation appears to have the most toxic effects when expressed in mice (Kahle et al. 2000; Matsuoka et al. 2001; Lee et al. 2002; Gomez-Isla et al. 2003). As well as mislocalization of α-synuclein (van der Putten et al. 2000; Giasson et al. 2002; Lee et al. 2002; Gispert et al. 2003) and severe progressive motor abnormalities (van der Putten et al. 2000; Giasson et al. 2002; Lee et al. 2002), A53T expression leads to pathological non-fibrillar (van der Putten et al. 2000; Lee et al. 2002; Gispert et al. 2003) and fibrillar (Giasson et al. 2002) accumulations of α-synuclein and ubiquitin (van der Putten et al. 2000; Giasson et al. 2002; Lee et al. 2002). Mitochondrial DNA damage and degeneration, including reduced complex IV activity, has also been observed in A53T α-synuclein mice (Martin et al. 2006).
Of note, mice expressing both mutations A53T and A30P do not show exacerbated pathological or motor phenotypes in comparison to the single mutant models described above (Richfield et al. 2002). In contrast, β-synuclein overexpression may ameliorate motor deficits, neurodegenerative alterations and the neuronal α-synuclein accumulation observed in human α-synuclein transgenic mice (Hashimoto et al. 2001). Endogenous mouse α-synuclein was also shown to be protective in a prion-promoted (mPrP) human A53T α-synuclein model when compared to the same mouse on an α-synuclein null background (Cabin et al. 2005).
Only somatic gene transfer in adults has provided models with neuronal cell loss. Adeno- or lenti-viral delivery of human wild type and mutant (A30P, A53T) α-synuclein to the substantia nigra of rats and primates leads to loss of dopaminergic neurons, α-synuclein inclusions and neuritic pathology (Kirik et al. 2002, 2003 Klein et al. 2002; Lo Bianco et al. 2002; Lauwers et al. 2003; Yamada et al. 2004) as well as ubiquitin-positive inclusions (Lauwers et al. 2003). Mild motor impairment assessed by drug-induced rotational behavior was also noted in two rat models (Kirik et al. 2002; Lauwers et al. 2003). Lentiviral delivery of wild type and A53T α-synuclein into the striatum and the amygdala induced similar changes to those seen after nigral delivery, indicating that the Lewy-like pathology and neurodegeneration are not restricted to dopaminergic cells (Lauwers et al. 2003).
A new player in PD; LRRK2
As one of the most important genetic causes of autosomal dominant late onset-PD, the discovery of mutations in leucine-rich repeat kinase 2 (LRRK2; Lrrk2) has undoubtedly opened a whole new gateway for PD animal models (Zimprich 2004). Postmortem analysis of patients from Family A harboring a Lrrk2 Y1699C mutation, and Family D with Lrrk2 R1441C, reveals pleomorphic pathology including neuronal loss with α-synuclein, tau and ubiquitin lesions (Zimprich 2004). However, the vast majority of brains with Lrrk2 G2019S, the most common mutation identified to date have transitional/brainstem restricted Lewy body pathology found in typical, late-onset idiopathic PD (Mata et al. 2005; Ross et al. 2006). Lrrk2 G2019S displays variable, age-associated penetrance (Kachergus et al. 2005; Kay et al. 2005). In silico modeling and recent in vitro data have shown Lrrk2 mutants G2019S and I2020T have increased kinase activity (Gloeckner et al. 2005; West et al. 2005). Aberrant Lrrk2 activity may impact both Ras and MAPK signaling and serves to highlight the potential importance of these pathways in idiopathic PD. We and others have recently shown that LRRK2 mRNA expression in mice is most abundant in dopamine-innervated areas, rather than the dopamine synthesizing neurons (Melrose et al. 2006; Simon-Sanchez et al. 2006) and highest in the striatum and the olfactory tubercle. The first Lrrk2 BAC model with physiologically and temporally relevant patterns of expression shows tau-positive neurodegenerative changes, reminiscent of that observed in some human patients with Lrrk2-associated disease (Dr. H.L. Melrose, personal communication at the World Congress of Parkinson’s disease, Feb 22–26, 2006). We postulate Lrrk2 is essential for dopaminergic neuronal survival whereas mutant Lrrk2 may diminish trophic support in the nigrostriatal pathway via disruption of proteins involved in synaptic release, trafficking or axonal retrograde transport.
Animal models of mutant or wild type LRRK2 will enable the biological function of Lrrk2 and its relevance to PD to be assessed. The synergistic effects of α-synuclein and tau may be studied on this background, given neuronal cell death, Lewy bodies and tauopathy are the major pathologies associated with LRRK2 mutations in man. The susceptibility of these models to epidemiologic and toxin exposures may be explored, as well as the efficacy of MAPK inhibition to prevent Lrrk2-induced neurodegenerative disease.
Time for a rethink
While many models of PD have been created to date no single model, either based on toxins or genetic, has been able to recreate all the key features of disease. Neurotoxins, herbicides, pesticides, fungicides and proteasomal inhibitors have been shown in varying capacity to induce some features of PD in rodents. These symptomatic models have provided considerable therapeutic insight into basal ganglia physiology and response to drug therapy. However, paraquat, rotenone and epoxomicin are systemic poisons and produce considerable morbidity and mortality and it remains unclear why the animals that survive have selective nigrostriatal deficits. In contrast, 6-OH-DOPA and MPTP are preferentially metabolized by dopaminergic neurons in which their effects are limited. Presently, it is also unknown whether genetic causes identified in rare, Mendelian forms of parkinsonism highlight pathways affected in idiopathic PD. Nevertheless, knock-out, overexpression and mutations in single genes provide a powerful new set of molecular tools to study etiology. Parkinson’s syndrome most likely results from an intricate combination of gene and gene–environment interactions. This is a complicated scenario that poses an exigent challenge for the animal modeler. An understanding of the limitations of current models in PD and what can be done to improve them is needed.
Firstly, we must better define what we are attempting to model. Although neurologists have primarily characterized PD as a movement disorder, this is a biased view. The reality is that multiple systems are affected. The earliest signs of PD typically occur in the gut with constipation in mid-life, with seborrhea in the skin, with sympathetic denervation of the heart and with anosmia of the olfactory bulbs (Fahn 2003). REM sleep behavior disorder and depression are also early features, possibly reflecting dysfunction in the dorsal raphe (Fahn 2003). Although seldom considered predictive, these clinical observations are not new; James Parkinson stated constipation and sleep disorder in his original 1817 diagnosis. The recent staging proposed by Braak highlights the burden of α-synuclein pathology in these anatomical sites (Braak et al. 2004).
Other than a progressive movement disorder, traditional models of PD require selective cell loss in the substantia nigra accompanied by end-stage Lewy body pathology. However, in patients Lewy bodies neither correlates with the movement disorder nor cognitive decline observed (Parkkinen et al. 2005). Even in SNCA mutant and multiplication families, the central issue may be temporal, regional and quantitative dysregulation of α-synuclein expression; normal expression of the protein plays an important role in response to toxic insults and environmental stress. As α-synuclein-positive Lewy bodies are only found in surviving neurons they may be protective rather than causal. Although an unorthodox and perhaps heretical view, recent work in Drosophila suggests α-synuclein phosphorylation is required for neurotoxicity, whereas non-phosphorylated protein has a propensity to form inclusion bodies (Chen and Feany 2005). In this light, a central focus on α-synuclein aggregates, fibrils, protofibrils, oligomeric or monomeric species and which are pathogenic may be misguided. While Lewy neurites are likely to be detrimental to neuronal connectivity, preventing α-synuclein expression or fibril formation, or disaggregation of existing inclusion bodies, may exacerbate the disease process.
Both toxic and transgenic models will help address this fundamental question and elucidate the dynamics of α-synuclein expression and aggregation in vivo. However, existing models suggest Lewy-like pathology is problematic to create. In mice, high wild type or mutant α-synuclein expression specifically targeted to the dopaminergic neurons of the substantia nigra via a tyrosine hydroxylase promoter does not result in pathology (Matsuoka et al. 2001), and in other models the nigra appears to be relatively spared even when pathogenic α-synuclein aggregates are present (Fernagut and Chesselet 2004). Although background strain may account for some of the differences between transgenic lines, this is difficult to assess given the variety of heterologous promoters employed. Differences in transgene integration site may influence α-synuclein expression pattern/levels. In addition, endogenous α-, β- and/or γ-synuclein expression, both across and within congenic strains, may developmentally compensate for human α-synuclein overexpression. The phenotype of progressive toxin models, including rotenone and epoxomicin, is also technically challenging to achieve and results are variable, as when animals survive they may not develop a lesion. These apparent differences in susceptibility/resistance may again be due to intra-strain variability.
Transgenic models with the most pronounced phenotypes have used promoters that direct inappropriately high α-synuclein expression in the brainstem and the spinal cord, but have little or no expression in the striatum although this structure is an integral component of the basal ganglia and displays considerable endogenous α-synuclein expression. No transgenic model yet reproduces the physiological expression pattern of α-synuclein, which in humans and mice is low in sub-cortical regions and higher in the cortex and limbic system (Rockenstein et al. 2002). BAC/PAC genetic models that rely on human gene promoters, coupled with recent advances in BAC/PAC mutagenesis, might now overcome this limitation (Sopher and La Spada 2006). The generation of ‘humanized mice’ via null crosses can also help achieve tissue-specific expression and appropriate post-translational protein modifications. For example, genomic PAC mice developed to model human tauopathy did not develop tau neurofibrillary pathology (Duff et al. 2000) until they were crossed onto a tau-null background (Andorfer et al. 2003).
If SNCA multiplication patients reflect the underlying molecular events in idiopathic PD, models created using a SNCA BAC transgenic approach may provide fundamental insight into the staging of α-synuclein pathology. Furthermore as transgene expression is not restricted to the brain, studies of peripheral tissues may have predictive value in human patients. In PD, non-motor symptoms clearly precede the onset of parkinsonism by many decades and if neuroprotection trials are to meet with success, early and accessible biomarkers of disease progression are essential. Models of α-synuclein biology may be especially insightful combined with toxin exposures, as they may help explain the reduced age-associated penetrance of familial PD. Lrrk2 models are being created, and while the function of this protein is yet unknown, insights gained from the development of α-synuclein and tau models and crosses with these lines should prove invaluable in exploring the pleomorphic pathology observed. Loss-of-function mutations in Parkin, DJ-1 and PINK1 clearly implicate impaired protein handling, oxidative stress and mitochondrial dysfunction as important players in dopamineric neurons and the pathogenesis of PD. However, genetic knockout of Parkin and DJ-1 in mouse models have subtle phenotypes. This may reflect the predominant movement phenotype in these patients that typically requires only low doses of l-DOPA to remedy; in contrast to idiopathic PD, non-motor and probably non-dopaminergic features are not as problematic. Chemically induced rodent models have long shown that mitochondrial complex I dysfunction has a selective effect on the nigrostrial system. Curiously, overexpression of Parkin or DJ-1 in combination with toxin exposure appears to provide some protective benefit. DJ-1 viral delivery into MPTP treated mice ameliorates striatal deficit and dopaminergic loss, whereas Parkin viral delivery rescues α-synucleinopathy in a rat model (Lo Bianco et al. 2004; Kim et al. 2005).
Thus, although parkinsonism may have many causes a finite number of overlapping pathways appear to be affected. Animal models allow those pathways to be explored and novel treatment strategies developed. The recent discovery of single gene defects that lead to the phenotype, including SNCA and LRRK2 provides the simplest and most powerful approach. Manipulating these endogenous genes, using knock-in and knock-out strategies and BAC methods may be most physiologically relevant, whereas inducible/regulatable transgene expression will address specific questions in limited tissues. In combination, and with toxin models, most of the features of PD can now be modeled, and with these tools both neuroprotective and symptomatic therapies can be developed.
References
Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252
Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259
Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494
Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134
Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22:8797–8807
Cabin DE, Gispert-Sanchez S, Murphy D, Auburger G, Myers RR, Nussbaum RL (2005) Exacerbated synucleinopathy in mice expressing A53T SNCA on a SNCA null background. Neurobiol Aging 26:25–35
Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE, Sudhof TC (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci USA 101:14966–14971
Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657–663
Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Ding Y, Carvey PM, Ling Z, Kang UJ, Zhuang X (2005) Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 280:21418–21426
Cory-Slechta DA, Thiruchelvam M, Barlow BK, Richfield EK (2005) Developmental pesticide models of the Parkinson disease phenotype. Environ Health Perspect 113:1263–1270
Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R (2002) Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 99:14524–14529
Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL (2004) Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology 25:761–769
Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, Malester B, Hutton M, Adamson J, Goedert M, Burki K, Davies P (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis 7:87–98
Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann NY Acad Sci 991:1–14
Fernagut PO, Chesselet MF (2004) Alpha-synuclein and transgenic mouse models. Neurobiol Dis 17:123–130
Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, Chesselet MF (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci 24:9434–9440
Frasier M, Walzer M, McCarthy L, Magnuson D, Lee JM, Haas C, Kahle P, Wolozin B (2005) Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol 192:274–287
Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533
Gispert S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, Korf HW, Deller T, Braak H, Auburger G, Nussbaum RL (2003) Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol Cell Neurosci 24:419–429
Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O’Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M (2005) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15:223–232
Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278:43628–43635
Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J (2005) Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45:489–496
Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S, Sondel J, Kotilinek L, Day J, Schwarzschild MA, Cha JH, Newell K, Miller DW, Ueda K, Young AB, Hyman BT, Ashe KH (2003) Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice. Neurobiol Aging 24:245–258
Hashimoto M, Rockenstein E, Mante M, Mallory M, Masliah E (2001) beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32:213–223
Hope A, Farrer M (2004) Genetics of α-synucleinopathy. In: Philipp K, Haass C (eds) Molecular mechanisms in Parkinson’s disease. Landes Bioscience, Georgetown
Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney TA, Brice A, Garcia de Yebenes J (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277–2291
Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M (1998) Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson’s disease mutation. J Biol Chem 273:26292–26294
Jeon BS, Jackson-Lewis V, Burke RE (1995) 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4:131–137
Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 76:672–680
Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Schindzielorz A, Okochi M, Leimer U, van Der Putten H, Probst A, Kremmer E, Kretzschmar HA, Haass C (2000) Subcellular localization of wild-type and Parkinson’s disease-associated mutant alpha -synuclein in human and transgenic mouse brain. J Neurosci 20:6365–6373
Kahle PJ, Neumann M, Ozmen L, Muller V, Odoy S, Okamoto N, Jacobsen H, Iwatsubo T, Trojanowski JQ, Takahashi H, Wakabayashi K, Bogdanovic N, Riederer P, Kretzschmar HA, Haass C (2001) Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 159:2215–2225
Kay DM, Kramer P, Higgins D, Zabetian CP, Payami H (2005) Escaping Parkinson’s disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 20:1077–1078
Khan NL, Brooks DJ, Pavese N, Sweeney MG, Wood NW, Lees AJ, Piccini P (2002) Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 125:2248–2256
Khan NL, Scherfler C, Graham E, Bhatia KP, Quinn N, Lees AJ, Brooks DJ, Wood NW, Piccini P (2005) Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation. Neurology 64:134–136
Kholodilov NG, Oo TF, Burke RE (1999) Synuclein expression is decreased in rat substantia nigra following induction of apoptosis by intrastriatal 6-hydroxydopamine. Neurosci Lett 275:105–108
Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, You-Ten AJ, Kalia SK, Horne P, Westaway D, Lozano AM, Anisman H, Park DS, Mak TW (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102:5215–5220
Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Bjorklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791
Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjorklund A (2003) Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA 100:2884–2889
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608
Klein RL, King MA, Hamby ME, Meyer EM (2002) Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther 13:605–612
Klivenyi P, Siwek D, Gardian G, Yang L, Starkov A, Cleren C, Ferrante RJ, Kowall NW, Abeliovich A, Beal MF (2005) Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol Dis 21:541–548. DOI 10.1016/j.nbd.2005.08.018
Kopin IJ, Markey SP (1988) MPTP toxicity: implications for research in Parkinson’s disease. Annu Rev Neurosci 11:81–96
Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980
Lauwers E, Debyser Z, Van Dorpe J, De Strooper B, Nuttin B, Baekelandt V (2003) Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. Brain Pathol. 13:364–372
Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 –> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968–8973
Lincoln S, Wiley J, Lynch T, Langston JW, Chen R, Lang A, Rogaeva E, Sa DS, Munhoz RP, Harris J, Marder K, Klein C, Bisceglio G, Hussey J, West A, Hulihan M, Hardy J, Farrer M (2003) Parkin-proven disease: common founders but divergent phenotypes. Neurology 60:1605–1610
Lo Bianco C, Ridet JL, Schneider BL, Deglon N, Aebischer P (2002) alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci USA 99:10813–10818
Lockhart PJ, O’Farrell CA, Farrer MJ (2004) It’s a double knock-out! The quaking mouse is a spontaneous deletion of parkin and parkin co-regulated gene (PACRG). Mov Disord 19:101–104
Lorenzetti D, Antalffy B, Vogel H, Noveroske J, Armstrong D, Justice M (2004) The neurological mutant quaking(viable) is Parkin deficient. Mamm Genome. 15:210–217
Lo Bioanco C, Schneider BL, Bauer M, Sajadi A, Brice A, Iwatsubo T, Aebischer P (2004) Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci USA 101:17510–17515
Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277:1641–1644
Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26:41–50
Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269
Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250
Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu RM, Lu CS, Lahoz C, Wszolek ZK, Farrer MJ (2005) LRRK2 pathogenic substitutions in Parkinson’s disease. Neurogenetics 6:171–177
Mata IF, Lockhart PJ, Farrer MJ (2004) Parkin genetics: one model for Parkinson’s disease. Hum Mol Genet 13(1):R127–R133
Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte DA (2001) Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 8:535–539
McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol 56:149–162
Melrose HL, Lincoln S, Tyndall G, Dickson D, Farrer M (2006) Anatomical localization of LRRK2 in mouse brain. Neuroscience (in press)
Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87
Nieto M, Gil-Bea FJ, Dalfo E, Cuadrado M, Cabodevilla F, Sanchez B, Catena S, Sesma T, Ribe E, Ferrer I, Ramirez MJ, Gomez-Isla T (2005) Increased sensitivity to MPTP in human alpha-synuclein A30P transgenic mice. Neurobiol Aging 7:7. DOI 10.1016/j.neurobiolaging.2005.04.010
Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I (2005) Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 57:82–91
Perez FA, Palmiter RD (2005) Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA 102:2174–2179
Perez FA, Curtis WR, Palmiter RD (2005) Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity. BMC Neurosci 6:71
Periquet M, Corti O, Jacquier S, Brice A (2005) Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. J Neurochem 95:1259–1276
Pramstaller PP, Schlossmacher MG, Jacques TS, Scaravilli F, Eskelson C, Pepivani I, Hedrich K, Adel S, Gonzales-McNeal M, Hilker R, Kramer PL, Klein C (2005) Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol 58:411–422
Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA (2005) Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol Dis 20:898–906
van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S., Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human alpha-synuclein. J Neurosci 20:6021–6029
Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW (2005) Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci 88:193–201
Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ (2002) Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol 175:35–48
Robertson DC, Schmidt O, Ninkina N, Jones PA, Sharkey J, Buchman VL (2004) Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice. J Neurochem 89:1126–1136
Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E (2002). Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 68:568–578
Ross OA, Farrer MJ (2005) Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson’s disease. Biochem Soc Trans 33:586–590
Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW (2006) LRRK2 and Lewy body disease. Ann Neurol 59:388–393
Schluter OM, Fornai F, Alessandri MG, Takamori S, Geppert M, Jahn R, Sudhof TC (2003) Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 118:985–1002
Schober A (2004) Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 318:215–224
Sedelis M, Schwarting RK, Huston JP (2001) Behavioral phenotyping of the MPTP mouse model of Parkinson’s disease. Behav Brain Res 125:109–125
Sherer TB, Betarbet R, Greenamyre JT (2002) Environment, mitochondria, and Parkinson’s disease. Neuroscientist 8:192–197
Sherer TB, Kim JH, Betarbet R, Greenamyre JT (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 179:9–16
Simon-Sanchez J, Herranz-Perez V, Olucha-Bordonau F, Perez-Tur J (2006) LRRK2 is expressed in areas affected by Parkinson’s disease in the adult mouse brain. Eur J Neurosci 23:659–666
Song DD, Shults CW, Sisk A, Rockenstein E, Masliah E (2004) Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol 186:158–172
Sopher BL, La Spada AR (2006) Efficient recombination-based methods for bacterial artificial chromosome fusion and mutagenesis. Gene 15:15
Specht CG, Schoepfer R (2001) Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci 2:24
Speciale SG (2002) MPTP: insights into parkinsonian neurodegeneration. Neurotoxicol Teratol 24:607–620
Steidl JV, Gomez-Isla T, Mariash A, Ashe KH, Boland LM (2003) Altered short-term hippocampal synaptic plasticity in mutant alpha-synuclein transgenic mice. Neuroreport 14:219–223
Tao X, Tong L (2003) Crystal structure of human DJ-1, a protein associated with early onset Parkinson’s disease. J Biol Chem 278:31372–31379
Twelves D, Perkins KS, Counsell C (2003) Systematic review of incidence studies of Parkinson’s disease. Mov Disord 18:19–31
Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S (2000) Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74:721–729
Von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, Dawson VL, Dawson TM (2004) Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci USA 101:10744–10749
Watanabe Y, Himeda T, Araki T (2005) Mechanisms of MPTP toxicity and their implications for therapy of Parkinson’s disease. Med Sci Monit 11:RA17–RA23
West A, Periquet M, Lincoln S, Lucking CB, Nicholl D, Bonifati V, Rawal N, Gasser T, Lohmann E, Deleuze JF, Maraganore D, Levey A, Wood N, Durr A, Hardy J, Brice A, Farrer M (2002) Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet 114:584–591
West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 102:16842–16847
Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H (2004) Overexpression of alpha-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson’s disease. J Neurochem 91:451–461
Yamada M, Mizuno Y, Mochizuki H (2005) Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson’s disease. Hum Gene Ther 16:262–270
Zeng BY, Dass B, Owen A, Rose S, Cannizzaro C, Tel BC, Jenner P, Kholodilov NG, Oo TF, Burke RE (2002) 6-Hydroxydopamine lesioning differentially affects alpha-synuclein mRNA expression in the nucleus accumbens, striatum and substantia nigra of adult rats
Zhang L, Shimoji M, Thomas B, Moore DJ, Yu SW, Marupudi NI, Torp R, Torgner IA, Ottersen OP, Dawson TM, Dawson VL (2005) Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 14:2063–2073
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607
Acknowledgements
This work was supported by Michael J Fox Fellowship to Dr. Heather Melrose and by research grants from the National Parkinson’s Foundation and the National Institute for Neurological Disease and Stroke (P01 NS40256).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Melrose, H.L., Lincoln, S.J., Tyndall, G.M. et al. Parkinson’s disease: a rethink of rodent models. Exp Brain Res 173, 196–204 (2006). https://doi.org/10.1007/s00221-006-0461-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-006-0461-3