Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity

Perez, Francisco A.; Curtis, Wendy; Palmiter, Richard D.

doi:10.1186/1471-2202-6-71

Cited by 59 publications

(21 citation statements)

References 67 publications

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“…In contrast, the study of Perez et al (Perez, et al, 2005) found no difference between wt and parkin KO mice in terms of sensitivity to METH toxicity, suggesting no role for parkin in mediating toxicity of the drug. It is possible that one of many other RING E3 ligases functioning in neurons takes over parkin functions in case of its deficit.…”

Section: Discussionmentioning

confidence: 86%

Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

Liu

Traini

Killinger

et al. 2013

Experimental Neurology

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Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity.

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Section: Discussionmentioning

confidence: 86%

Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

Liu

Traini

Killinger

et al. 2013

Experimental Neurology

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“…To further assess the role of parkin in regulation of UCH-L1 ubiquitination in vivo , we examined the ubiquitination status of endogenous UCH-L1 in brains from wild type ( parkin +/+ ) and parkin knockout ( parkin −/− ) mice [49,50] by using the tandem ubiquitin binding entities (TUBEs) approach. Previous studies have shown that GST-tagged TUBEs, such as GST-tagged TUBE2 based on the UBA1 domain from human RAD23A, preferentially capture endogenous poly-ubiquitinated proteins, but bind monoubiquitinated proteins at much lower affinity [51].…”

Section: Resultsmentioning

confidence: 99%

“…A breeding colony of parkin knockout ( parkin −/− ) mice was established from breeding pairs provided by R. Palmiter, University of Washington, Seattle, WA [49,50]. For assessment of endogenous UCH-L1 ubiquitination in parkin −/− and parkin +/+ mouse brain, immobilized GST-tagged, tandem ubiquitin binding entities (GST-TUBE2, LifeSensors) were used as described [51] to isolate ubiquitinated proteins from brain extracts from 4-month-old male parkin −/− mice and wild type controls, followed by immunoblotting with anti-UCH-L1 and anti-GST antibodies.…”

Section: Methodsmentioning

confidence: 99%

Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system

McKeon

Sha

et al. 2014

Cell. Mol. Life Sci.

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Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a key neuronal deubiquitinating enzyme which is mutated in Parkinson disease (PD) and in childhood-onset neurodegenerative disorder with optic atrophy. Furthermore, reduced UCH-L1 protein levels are associated with a number of neurodegenerative diseases, whereas up-regulation of UCH-L1 protein expression is found in multiple types of cancer. However, very little is known about how UCH-L1 protein level is regulated in cells. Here, we report that UCH-L1 is a novel interactor and substrate of PD-linked E3 ubiquitin-protein ligase parkin. We find that parkin mediates K63-linked polyubiquitination of UCH-L1 in cooperation with the Ubc13/Uev1a E2 ubiquitinconjugating enzyme complex and promotes UCH-L1 degradation by the autophagy-lysosome pathway. Targeted disruption of parkin gene expression in mice causes a significant decrease in UCH-L1 ubiquitination with a concomitant increase in UCH-L1 protein level in brain, supporting an in vivo role of parkin in regulating UCH-L1 ubiquitination and degradation. Our findings reveal a direct link between parkin-mediated ubiquitin signaling and UCH-L1 regulation, and they have important implications for understanding the roles of these two proteins in health and disease.

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“…6G-H). PK-KO mice are more susceptible than WT to ROT and the Metamphetamine Similar Lower DAT levels [182] Rotenone Increased Higher susceptibility to mitochondrial damage and microglial activation [103,183] combined effects of Park-2 suppression and ROT reproduces the cellular events observed in PD. These events were prevented by minocycline.…”

Section: Genes and Environmental Neurotoxinsmentioning

confidence: 96%

On the Pathogenesis and Neuroprotective Treatment of Parkinson Disease: What have we Learned from the Genetic Forms of this Disease?

Mena¹,

Rodríguez-Navarro

Ros³

et al. 2008

CMC

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Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease. More recently, genetic alterations have been found in patients with PD. The function of the proteins coded by the genes involved in PD has been investigated in genetic models of this disease from invertebrate to rodents. Mutated proteins responsible for PD have been tested in vivo and in vitro, in cellular models or in artificial constructs. A wealth of important information about the function of alpha-synuclein, parkin, DJ-1, PINK and dardarin is available, most notably about the first two causes of familial PD discovered, alpha-synuclein and parkin, responsible for autosomal dominant and autosomal recessive PD, respectively. Different animal models of alpha-synuclein and parkin have been extensively investigated. The in vitro and in vivo studies performed in genetic models of PD have shown that the proteins involved in the pathogenesis of PD interact with one another and have multiple mechanisms of cell toxicity. From the available data, it is clear that the mechanisms leading to cell degeneration in PD are variable in the different subtypes of this disease. Neuroprotective therapies should, therefore, be multiple and tailored according to the factors involved in the different cases. In this study, we review what we have learned from the genetic models of PD and the putative strategies to be tested in the near future.

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Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity

Cited by 59 publications

References 67 publications

Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system

On the Pathogenesis and Neuroprotective Treatment of Parkinson Disease: What have we Learned from the Genetic Forms of this Disease?

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