Transgenic rodent models of Parkinson’s disease

Harvey, Brandon K.; Wang, Y.; Hoffer, Barry J.

doi:10.1007/978-3-211-78205-7_15

Cited by 36 publications

(26 citation statements)

References 47 publications

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“…A recent study indicates that this is not the case for 6-OHDA lesions in mice, which yield massive and long lasting reductions in the residual DA content within the striatum, as well as in the number of TH positive cells in the substantia nigra in all mice tested 10 .…”

Section: Discussionmentioning

confidence: 96%

Murine Model for Parkinson's Disease: from 6-OH Dopamine Lesion to Behavioral Test

Conceição

Ngo-Abdalla

Houzel

et al. 2010

JoVE

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Parkinson's disease (PD) affects at least 6.5 million people worldwide, irrespective of gender, social, ethnic, economic, or geographic boundaries. Key symptoms, such as tremor, rigidity and bradikinesia, develop when about 3/4 of dopaminergic cells are lost in the substantia nigra, and fail to provide for the smooth, coordinated regulation of striatal motor circuits. Depression and hallucinations are common, and dementia eventually occurs in 20% of patients. At this time, there is no treatment to delay or stop the progression of PD. Rather, the medications currently available aim more towards the alleviation of these symptoms. New surgical strategies may reversibly switch on the functionally damaged circuits through the electrical stimulation of deep brain structures, but although deep brain stimulation is a major advance, it is not suitable for all patients. It remains therefore necessary to test new cell therapy approaches in preclinical models.Selective neurotoxic disruption of dopaminergic pathways can be reproduced by injection of 6-hydroxydopamine (6-OHDA) or MPTP (1-methyl-4-phenyl-1,2,3,6-tertahydropyridine) whereas depleting drugs and oxidative-damaging chemicals may also reproduce specific features of PD in rodents. Unlike MPTP, 6-OHDA lesions cause massive irreversible neuronal loss, and can be uni-or bilateral. The 6-OHDA lesion model is reliable, leads to robust motor deficits, and is the most widely used after 40 years of research in rats1. As interactions between grafted cells and host can now be studied more thoroughly in mice rather than in rats, the model has been transposed to mice 2,3 , where it has been recently characterized 4 .In this video, we demonstrate how to lesion the left nigro-striatal pathway of anesthetized mice by slowly delivering 2.0 μL of 6-OHDA through a stereotaxically inserted micro-syringe needle. The loss of dopaminergic input occurs within days, and the functional impairments can be monitored over post-operative weeks and months by rating animal rotations induced by dopaminergic agents 5 . Here, we show full-body contralateral rotations occurring 10 minutes after a single subcutaneous administration of apomorphine, measured one month after the lesion. Outcomes and drawbacks are discussed below. ProtocolAll chemicals stored in solid form, such as 6-OHDA and apomorphine, were diluted in sterile injection water and filtered inside a laminar flow hood, to avoid contamination. In addition, neurotoxins and neuroactive substances were stored, prepared, handled and disposed according to regulations set by international guidelines 6 and the local Biosafety Committee. -Anesthesia and surgeryAdult male Swiss mice (25-30g) are premedicated with Atropine (0.2 mg/Kg, s.c.) to reduce vagal tone and then anesthetized with an intraperitoneal injection of Ketamine (90-120 mg/Kg) and Xylazine (10 mg/Kg). The animal is placed on an electronically controlled heating pad (Insight) to ensure body temperature is maintained at 37°C, as induction of sedation takes some minutes. The anes...

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Section: Discussionmentioning

confidence: 96%

Murine Model for Parkinson's Disease: from 6-OH Dopamine Lesion to Behavioral Test

Conceição

Ngo-Abdalla

Houzel

et al. 2010

JoVE

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“…Functional compensation in Parkin null mice is also observed in neurological tissue 24 and can explain minimal cardiac and neurological phenotypes. 16,35 As Drosophila have only 1 Parkin-like protein (Parkin), 11 fruit flies are excellent models of Parkin dysfunction, perhaps explaining why the major mechanistic insights into Parkin-mediated mitophagy and its role in Parkinson disease have derived from work in Drosophila . 6,7,11–14 Our observation that homozygous and heterozygous germline parkin gene ablation and cardiomyocyte-specific Parkin suppression in fruit flies are each detrimental to mitochondrial and cardiac health suggests that a genetic approach in mice that minimizes the opportunity for compensatory regulation of putative alternate mitophagy pathways, such as cardiac-specific Parkin gene ablation, is likely to offer a different view of Parkin’s role in the mammalian heart.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin

Bhandari¹,

Song²,

Chen³

et al. 2014

Circulation Research

122

116

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Rationale Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood. Objective We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in Drosophila heart tubes. Methods and Results Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because Drosophila lack most of these redundant genes, we examined heart tubes of parkin knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy. Conclusions Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by inhibiting organelle fusion shows promise for minimizing organ dysfunction produced by defective mitophagic signaling.

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“…Many lines of PD-related mutant α-syn transgenic mice have been generated previously; however, few of them exhibited robust and progressive degeneration of mDA neurons (Kahle et al, 2001;van der et al, 2000;Matsuoka et al, 2001;Lee et al, 2002;Lin et al, 2009;Chesselet, 2008;Harvey et al, 2008;Richfield et al, 2002;Gispert et al, 2003;Wakamatsu et al, 2008;Thiruchelvam et al, 2004). Noticeably, only a scarce or low levels of transgenic α-syn expression were observed in the mDA neurons of these mutant mice, in which the transgenic α-syn is often under the transcriptional control of pan neuronal promoters or a rat tyrosine hydroxylase ( TH ) promoter.…”

Section: Introductionmentioning

confidence: 99%

Conditional Expression of Parkinson's Disease-Related Mutant -Synuclein in the Midbrain Dopaminergic Neurons Causes Progressive Neurodegeneration and Degradation of Transcription Factor Nuclear Receptor Related 1

Lin

Parisiadou

Sgobio

et al. 2012

Journal of Neuroscience

170

189

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α-synuclein(α-syn) plays a prominent role in the degeneration of midbrain dopaminergic (mDA) neurons in Parkinson disease (PD). However, only a few studies on α-syn have been carried out in the mDA neurons in vivo, which may be attributed to a lack of α-syn transgenic mice that develop PD-like severe degeneration of mDA neurons. To gain mechanistic insights into the α-syn-induced mDA neurodegeneration, we generated a new line of tetracycline-regulated inducible transgenic mice that overexpressed the PD-related α-syn A53T missense mutation in the mDA neurons. Here we show that the mutant mice developed profound motor disabilities and robust mDA neurodegeneration, resembling some key motor and pathological phenotypes of PD. We further systematically examined the subcellular abnormalities appeared in the mDA neurons of mutant mice, and observed a profound decrease of dopamine release, the fragmentation of Golgi apparatus, and impairments of autophagy/lysosome degradation pathways in these neurons. To further understand the specific molecular events leading to the α-syn-dependent degeneration of mDA neurons, we found that over-expression of α-syn promoted a proteasome-dependent degradation of nuclear receptor related 1 protein (Nurr1); while inhibition of Nurr1 degradation ameliorated the α-syn-induced loss of mDA neurons. Given that Nurr1 plays an essential role in maintaining the normal function and survival of mDA neurons, our studies suggest that the α-syn-mediated suppression of Nurr1 protein expression may contribute to the preferential vulnerability of mDA neurons in the pathogenesis of PD.

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Transgenic rodent models of Parkinson’s disease

Cited by 36 publications

References 47 publications

Murine Model for Parkinson's Disease: from 6-OH Dopamine Lesion to Behavioral Test

Murine Model for Parkinson's Disease: from 6-OH Dopamine Lesion to Behavioral Test

Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin

Conditional Expression of Parkinson's Disease-Related Mutant -Synuclein in the Midbrain Dopaminergic Neurons Causes Progressive Neurodegeneration and Degradation of Transcription Factor Nuclear Receptor Related 1

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