Genetic Rat Models of Parkinson's Disease

Welchko, Ryan; Lévèque, Xavier; Dunbar, Gary

doi:10.1155/2012/128356

Cited by 13 publications

(22 citation statements)

References 28 publications

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“…To date, genetic approaches in the rat have been largely limited to surgical approaches (Welchko, et al, 2012). Additional BAC-transgenic rat models of PD are expected to be characterized in the near future.…”

Section: Discussionmentioning

confidence: 99%

“…Current genetic rat models have typically utilized viral vector-based approaches that require intracerebral infusion (Welchko, et al, 2012), a surgical procedure that does not transduce all relevant neurons and does not elicit effects throughout the entire lifespan. Bacterial artificial chromosomal (BAC) technology has allowed for the production of transgenic rodents with over-expression levels much closer to physiological levels (~2–5 fold).…”

Section: Introductionmentioning

confidence: 99%

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Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment

Cannon¹,

Geghman²,

Tapias³

et al. 2013

Experimental Neurology

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Parkinson’s disease (PD), the second most common neurodegenerative disorder, is etiologically heterogeneous, with most cases thought to arise from a combination of environmental factors and genetic predisposition; about 10% of cases are caused by single gene mutations. While neurotoxin models replicate many of the key behavioral and neurological features, they often have limited relevance to human exposures. Genetic models replicate known disease-causing mutations, but are mostly unsuccessful in reproducing major features of PD. In this study, we created a BAC (bacterial artificial chromosome) transgenic rat model of PD expressing the E46K mutation of α-synuclein, which is pathogenic in humans. The mutant protein was expressed at levels ~2–3-fold above endogenous α-synuclein levels. At 12 months of age, there was no overt damage to the nigrostriatal dopamine system; however, (i) alterations in striatal neurotransmitter metabolism, (ii) accumulation and aggregation of α-synuclein in nigral dopamine neurons, and (iii) evidence of oxidative stress suggest this model replicates several preclinical features of PD. Further, when these animals were exposed to rotenone, a mitochondrial toxin linked to PD, they showed heightened sensitivity, indicating that α-synuclein expression modulates the vulnerability to mitochondrial impairment. We conclude that these animals are well-suited to examination of gene-environment interactions that are relevant to PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment

Cannon¹,

Geghman²,

Tapias³

et al. 2013

Experimental Neurology

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show abstract

“…These are genetic mouse models, primarily based on rare familial forms of PD (i.e., LRRK2 mutations, a-Syn mutation/overexpression, and parkin knockout), genetic rat models (i.e., LRRK2, a-Syn mutations), adeno-associated virus (AAV)-mediated overexpression of a-Syn, and toxin models (primarily 6-OHDA lesions in rats, MPTP lesions in mice, and nonhuman primates). 134 Whereas all of these models have their respective strengths and weaknesses, one lingering issue with the genetic models is that they have not been able to reliably capture the neurochemical and anatomical pathology of PD (including the degeneration of A9 dopamine neurons), and these animals do not display typical parkinsonian motor signs. Although some pathology 135 and neurotransmitter changes have been described in genetic models, particularly at advanced ages, 136,137 for the most part, these models have been described as modeling "premanifest PD."…”

Section: Modeling the Cognitive Dysfunction In Pdmentioning

confidence: 99%

The neurobiological basis of cognitive impairment in Parkinson's disease

et al. 2014

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The recent formalization of clinical criteria for PD with dementia (PD-D) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PD-D occurs on the background of severe dopamine deficits with the main pathological drivers of cognitive decline being a synergistic effect between α -synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the α-synuclein gene, lead to a clear increased risk of PD-D, while others, such as parkin mutations, are associated with a reduced risk of PD-D. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. While dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies and genetic factors in PD-MCI remain to be fully elucidated.

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“…Parkinson’s disease is due to a progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta . The striatum is the primary projection field of these substantia nigra neurons, thus the loss of DA results in insufficient stimulation of striatal dopaminergic D 1 and D 2 receptors ( 80 , 81 ). Decreased availability of DA triggers the symptomatic triad of bradykinesia, tremors-at-rest, and rigidity.…”

Section: Current Hypotheses Of Parkinson’s Diseasementioning

confidence: 99%

A Role for the Brain RAS in Alzheimer’s and Parkinson’s Diseases

2013

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The brain renin-angiotensin system (RAS) has available the necessary functional components to produce the active ligands angiotensins II (AngII), angiotensin III, angiotensins (IV), angiotensin (1–7), and angiotensin (3–7). These ligands interact with several receptor proteins including AT1, AT2, AT4, and Mas distributed within the central and peripheral nervous systems as well as local RASs in several organs. This review first describes the enzymatic pathways in place to synthesize these ligands and the binding characteristics of these angiotensin receptor subtypes. We next discuss current hypotheses to explain the disorders of Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as research efforts focused on the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), in their treatment. ACE inhibitors and ARBs are showing promise in the treatment of several neurodegenerative pathologies; however, there is a need for the development of analogs capable of penetrating the blood-brain barrier and acting as agonists or antagonists at these receptor sites. AngII and AngIV have been shown to play opposing roles regarding memory acquisition and consolidation in animal models. We discuss the development of efficacious AngIV analogs in the treatment of animal models of AD and PD. These AngIV analogs act via the AT4 receptor subtype which may coincide with the hepatocyte growth factor/c-Met receptor system. Finally, future research directions are described concerning new approaches to the treatment of these two neurological diseases.

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Genetic Rat Models of Parkinson's Disease

Cited by 13 publications

References 28 publications

Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment

Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment

The neurobiological basis of cognitive impairment in Parkinson's disease

A Role for the Brain RAS in Alzheimer’s and Parkinson’s Diseases

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