Resistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP

Abstract

Parkinson's disease (PD) is most commonly a sporadic illness, and is characterized by degeneration of substantia nigra dopamine (DA) neurons and abnormal cytoplasmic aggregates of ␣-synuclein. Rarely, PD may be caused by missense mutations in ␣-synuclein. MPTP, a neurotoxin that inhibits mitochondrial complex I, is a prototype for an environmental cause of PD because it produces a pattern of DA neurodegeneration that closely resembles the neuropathology of PD. Here we show that ␣-synuclein null mice display striking resistance to MPTP-induced degeneration of DA neurons and DA release, and this resistance appears to result from an inability of the toxin to inhibit complex I. Contrary to predictions from in vitro data, this resistance is not due to abnormalities of the DA transporter, which appears to function normally in ␣-synuclein null mice. Our results suggest that some genetic and environmental factors that increase susceptibility to PD may interact with a common molecular pathway, and represent the first demonstration that normal ␣-synuclein function may be important to DA neuron viability.T he concept of genetic predisposition to disease suggests that one's genes influence susceptibility to environmental insult. However, the relationship between genetic and environmental factors is poorly understood; most models of disease focus on single genes or toxins. A major challenge of postgenomic biology will be to link the molecular pathways modified by diseaseassociated alleles to the environmental factors implicated in disease susceptibility.There is increasing evidence for genetic susceptibility to Parkinson's disease (PD) (1-3). Additionally, dysfunction of a common molecular pathway has been implicated in the familial and sporadic forms of PD. Mutations in the gene that encodes ␣-synuclein cause a rare form of dominantly inherited PD, and ␣-synuclein is an abundant protein in Lewy bodies, the proteinaceous neuronal inclusions that are the pathological hallmark of sporadic PD (4-6). The ␣-synuclein pathway is also implicated in an autosomal recessive form of PD caused by mutations in the gene encoding parkin (7,8). Epidemiological and twin studies suggest that environmental factors alter susceptibility to PD (9). The fact that exposure of humans to the environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a syndrome that mimics the core neurological symptoms and relatively selective dopamine (DA) neuron degeneration of PD lends support to this concept (10, 11).We asked whether a model neurotoxin for an environmental cause of PD might act on a molecular pathway implicated in genetic and sporadic forms of the disease by generating ␣-synuclein null mice, and testing whether they display altered sensitivity to MPTP-induced degeneration of substantia nigra (SN) DA neurons. MethodsAnimal Generation. A 5.7-kb EcoRV mouse ␣-synuclein fragment (Fig. 1A) was used to generate the targeting construct. A DNA fragment containing, in order, LoxP-phosphoglycerate kinaseNeomycin-transcription blocking '...

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…MPTP, a known selective dopaminergic neurotoxin that inhibits mitochondrial complex I activity (as mentionedabove) creates an oxidative stress environment that enhances alphaͲsyn aggregation and consequent death of dopaminergic neurons [176]. Moreover, Dauer and colleagues [179] investigated the toxic effect of MPTP in mice lacking SNCA gene and concluded that these animals were resistant to MPTP, giving support to alphaͲsyn critical role in the pathogenesis of toxinͲinduced dopaminergic neuron death. A recent study performed by Kalivendi et al [180] demonstrated that oxidantͲinduced alternative splicing of alphaͲsyn plays a crucial role in the mechanism of dopamineneuron cell death, contributing to PD.…”

Lewy bodies

“…Four lines of ␣-SYN KO mice have been demonstrated to be resistant to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is a mitochondrial inhibitor relatively selective for the nigrostriatal DA system (11,66,67), and the protective effect appeared to be upstream of the mitochondria (66).…”

Transcriptional dysregulation in a transgenic model of Parkinson disease

“…Transgenic mice expressing mutant or wildtype α-syn show motor deficits, alterations in dopamine levels, and α-syn-positive inclusions (Hashimoto et al, 2003;Maries et al, 2003). Alpha-syn is also involved in the action of neurotoxins, such as MPTP and rotenone, used to model PD (Dauer et al, 2002;Betarbet et al, 2000).…”