Parkin Protects against Neurotoxicity in the 6-Hydroxydopamine Rat Model for Parkinson's Disease

Laboratory for Neurobiology and Gene Therapy, Molecular Medicine, K.U. Leuven, Kapucijnenvoer 33 VCTB+5, B-3000 Leuven, Flanders, Belgium.
Molecular Therapy (Impact Factor: 6.23). 12/2006; 14(5):716-23. DOI: 10.1016/j.ymthe.2006.06.009
Source: PubMed


Loss-of-function mutations in the PARK2 gene are the major cause of early onset familial Parkinson's disease. The gene product, parkin, is an E3 ligase of the ubiquitin-proteasome pathway involved in protein degradation. Dopaminergic neuron loss may result from the toxic accumulation of parkin substrates, suggesting a key role for parkin in dopaminergic neuron survival. In this study, we have investigated the neuroprotective capacity of parkin in the 6-OHDA rat model for Parkinson's disease. 6-OHDA induces the generation of reactive oxygen species leading to the degeneration of catecholaminergic neurons, but may also impair proteasome activity. Lentiviral vectors encoding human wild-type parkin or green fluorescent protein were stereotactically injected into the substantia nigra 2 weeks prior to a striatal 6-OHDA lesion. Histological analysis 1 and 3 weeks after lesioning showed a significant preservation of dopaminergic cell bodies and nerve terminals. Moreover, lesioned rats overexpressing parkin displayed a corresponding behavioral improvement as measured by the amphetamine-induced rotation test and the cylinder test. The improved performance in the amphetamine-induced rotation test lasted until 20 weeks after lesioning. Our results demonstrate that parkin acts as a potent neuroprotective agent in vivo against 6-OHDA toxic insults. These data support the therapeutic potential of parkin for the treatment of not only familial but also sporadic Parkinson's disease.

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    • "Although the molecular details of the relation between Parkin mutations and PD pathogenesis are not fully understood, a crucial role has been ascribed to the neuroprotective effect of Parkin via mitochondrial quality control (Chan and Chan, 2011; Pickrell and Youle, 2015). Accordingly, the beneficial role of Parkin expression was demonstrated by experiments using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-as well as 6-hydroxydopamine-induced neurodegeneration (Vercammen et al., 2006; Bian et al., 2012). Parkin mutations are associated to almost half of all early-onset PD cases (Lücking et al., 2000), usually causing a young average age at disease onset, nigral degeneration, absence of Lewy bodies and PD-specific motor deficits that show good response to L-DOPA therapy (Kitada et al., 2000; Lücking et al., 2000). "
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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non-dopaminergic neurotransmitter systems in PD. Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Quantitative receptor autoradiography was used to characterize 19 different receptor binding sites in eleven brain regions in order to understand receptor changes on a systemic level. We demonstrated striking differential changes of neurotransmitter receptor densities for numerous receptor types and brain regions, respectively. Most prominent, a strong up-regulation of GABA receptors and associated benzodiazepine binding sites in different brain regions and concomitant down-regulations of striatal nicotinic acetylcholine and serotonergic receptor densities were found. Furthermore, the densities of glutamatergic kainate, muscarinic acetylcholine, adrenergic α1 and dopaminergic D2/D3 receptors were differentially altered. These results present novel insights into the expression of neurotransmitter receptors in Pitx3(ak) mice supporting findings on PD pathology in patients and indicating on the possible underlying mechanisms. The data suggest Pitx3(ak) mice as an appropriate new model to investigate the role of neurotransmitter receptors in PD. Our study highlights the relevance of non-dopaminergic systems in PD and for the understanding of its molecular pathology. Copyright © 2014. Published by Elsevier Ltd.
    Full-text · Article · Nov 2014 · Neuroscience
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    • "We have not found any other reported experiments to study the effect and mechanism of puerarin on rotenone-induced cellular or animal models. We chose rotenone to induce dopaminergic neuron damage because of these three reasons: (1) the toxin of 6-OHDA is supervirulent, easier to induce acute toxicity (Blandini et al., 2008); (2) no a-synuclein overexpression was observed in the mostly used 6-OHDA models (Sachs and Jonsson, 1975; Vercammen et al., 2006); (3) the neurotoxin MPTP has species selectivity as it is more effective to induce parkinsonian symptoms in monkey and mouse than in rats (Hunot et al., 1997; Schmidt and Ferger, 2001; Xiong et al., 2009; Xiong et al., 2012). Puerarin is a natural product and traditional Chinese medicine that has been widely used for the treatment of cardiovascular, cerebrovascular diseases and alcohol toxicity for many years (Fan et al., 1984; Overstreet et al., 2003; Xu et al., 2005). "
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    ABSTRACT: It has been acknowledged that oxidative stress, resulting in the apoptosis of dopaminergic neurons, is a key mechanism in the pathogenesis of Parkinson's disease (PD). Puerarin, extracted from the root of pueraria lobata, has been clinically used for ischemic heart disease and cerebrovascular diseases as an oxygen free radical scavenger. In this study, we aimed to explore the effect of puerarin on dopaminergic cells degeneration in vitro and in vivo and its possible underlying mechanisms. In SH-SY5Y cells, the reduction of cell viability, apoptosis rate and average DCFH-DA fluorescence intensity of puerarin-treated (0, 10, 50, 100 and 150 μM) cells were significantly lower than control group. In rotenone-based rodent models, puerarin treatment for 7 days ameliorated apomorphine-induced rotations significantly in Pue-50 and Pue-100 group by 45.65% and 53.06% in the first week, by 44.60% and 48.45% in the second week. Moreover, compared to control group, puerarin increased tyrosine hydroxylase (TH) expression in the substantia nigra by 85.52% and 84.26% in Pue-50 group and Pue-100 group, and upregulated the vesicular monoamine transporter 2 (VMAT2) by 41.24% in Pue-50 group and 35.20% in Pue-100 group, and decreased ubiquitin expression by 47.55% in Pue-50 group and 69.15% in Pue-100 group. These data indicated that puerarin alleviated the oxidative stress and apoptosis in a PD cellular model, protected the dopaminergic neurons against rotenone toxicity and decreased the abnormal protein overexpressing in PD animal models. These findings suggest that puerarin may develop into a neuroprotective alternative for patients with PD.
    Full-text · Article · Sep 2014 · Neuroscience
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    • "The exact cellular function of DJ-1 remains uncertain, but it has been reported to be an atypical peroxiredoxin-like peroxidase (Andres-Mateos et al., 2007) and may be a sensor of oxidative stress (Choi et al., 2006). Overexpression of either protein is neuroprotective in vitro and in vivo (Bian et al., 2012; Hayashi et al., 2009; Junn et al., 2009; Lo Bianco et al., 2004; Ulusoy and Kirik, 2008; Vercammen et al., 2006; Zhou and Freed, 2005). In particular, DJ-1 is protective against various oxidative stresses (Andres-Mateos et al., 2007; Junn et al., 2009; Kim et al., 2005; Menzies et al., 2005; Meulener et al., 2005; Moore et al., 2005; Taira et al., 2004; Yang et al., 2005; Yokota et al., 2003; Zhang et al., 2005) and both proteins localize to mitochondria in cells undergoing oxidative stress (Horowitz and Greenamyre, 2010; Kawajiri et al., 2010; Shulman et al., 2011; Thomas et al., 2011). "
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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder behind Alzheimer's disease. There are currently no therapies proven to halt or slow the progressive neuronal cell loss in PD. A better understanding of the molecular and cellular causes of PD is needed to develop disease-modifying therapies. PD is an age-dependent disease that causes the progressive death of dopamine-producing neurons in the brain. Loss of substantia nigra dopaminergic neurons results in locomotor symptoms such as slowness of movement, tremor, rigidity and postural instability. Abnormalities in other neurotransmitters, such as serotonin, may also be involved in both the motor and non-motor symptoms of PD. Most cases of PD are sporadic but many families show a Mendelian pattern of inherited parkinsonism and causative mutations have been identified in genes such as Parkin, DJ-1, PINK1, alpha-synuclein and Leucine Rich Repeat Kinase 2 (LRRK2). Although the definitive causes of idiopathic PD remain uncertain, the activity of the antioxidant enzyme glutathione peroxidase 1 (Gpx1) is reduced in PD brains and has been shown to be a key determinant of vulnerability to dopaminergic neuron loss in PD animal models. Furthermore, Gpx1 activity decreases with age in human substantia nigra but not rodent substantia nigra. Therefore, we crossed mice deficient for both Parkin and DJ-1 with mice deficient for Gpx1 to test the hypothesis that loss-of-function mutations in Parkin and DJ-1 cause PD by increasing vulnerability to Gpx1 deficiency. Surprisingly, mice lacking Parkin, DJ-1 and Gpx1 have increased striatal dopamine levels in the absence of nigral cell loss compared to wild-type, Gpx1(-/-), and Parkin(-/-)DJ-1(-/-) mutant mice. Additionally, Parkin(-/-)DJ-1(-/-) mice exhibit improved rotarod performance and have increased serotonin in the striatum and hippocampus. Stereological analysis indicated that the increased serotonin levels were not due to increased serotonergic projections. The results of our behavioral, neurochemical and immunohistochemical analyses reveal that PD-linked mutations in Parkin and DJ-1 cause dysregulation of neurotransmitter systems beyond the nigrostriatal dopaminergic circuit and that loss-of-function mutations in Parkin and DJ-1 lead to adaptive changes in dopamine and serotonin especially in the context of Gpx1 deficiency.
    Full-text · Article · Sep 2013 · Neurobiology of Disease
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