Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease

Decressac, Mickaël; Mattsson, Bengt; Björklund, Anders

doi:10.1016/j.expneurol.2012.02.012

Cited by 119 publications

(98 citation statements)

References 29 publications

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“…Lentiviral vectors expressing human wild type or mutant forms of α-synuclein have been shown to lead to a progressive loss of nigral dopaminergic neurons by 24-35% in rats over 5 months 37 whereas adenoviruses expressing human α-synuclein have been shown to decrease nigral dopaminergic neurons by up to 80% in as short as 6 weeks, however these results are less consistent. 11,12,[38][39][40][41] In our model, miR-7T-AsRed significantly reduced TH expression by one-third at week 16 and two thirds at week 24. However, staining with VMAT2, another neuronal marker showed that there was only a 30% loss of neurons at 24 weeks suggesting that the nigral neurons had downregulated their activity.…”

Section: Discussionmentioning

confidence: 55%

“…4,5,[11][12][13][14] However, there has been much controversy about the form of α-synuclein that could be toxic to neurons. Oligomers of α-synuclein as well as truncations and posttranslational modifications have been shown to play an important role in neuronal toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…10 Furthermore, overexpression of α-synuclein has been found to be toxic to dopaminergic neurons, implicating α-synuclein as a key player in the molecular mechanisms of the disease. [11][12][13][14] The mechanisms underlying α-synuclein toxicity are unclear but one hypothesis is that α-synuclein may be acting in the manner of a prion: transferring from cell-to-cell, thus spreading pathology. Braak and colleagues were the first to suggest that α-synuclein might be spreading throughout the brain with Lewy pathology first appearing in the dorsal motor nucleus of the vagal nerve and the olfactory bulb.…”

Section: Introductionmentioning

confidence: 99%

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Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

et al. 2017

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms show that miR-7 is decreased in the substantia nigra of patients with PD and therefore may play an essential role in the regulation of α-synuclein expression. Furthermore, we have found that lentiviral mediated expression of miR-7 complementary binding sites to stably induce a loss of miR-7 function results in an increase in α-synuclein expression in vitro and in vivo. We have also shown that depletion of miR-7 using a miR-decoy produces a loss of nigral dopaminergic neurons accompanied by a reduction of striatal dopamine content. These data suggest that miR-7 has an important role in the regulation of α-synuclein and dopamine physiology and may provide a new paradigm to study the pathology of PD.3

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

et al. 2017

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“…Adeno-associated virus (AAV) vector-mediated overexpression of human wild-type α-syn in the rat midbrain, resulting in a three-to fourfold increase in α-syn mRNA (41), has previously been shown to induce PD-like neuropathology in nigral DA neurons, including accumulation of α-syn inclusions and progressive development of degenerative changes in axons and cell bodies that replicate both presymptomatic and advanced stages as seen in the human condition (41)(42)(43). To what extent these changes reflect alterations in ALP processing, however, is so far not known.…”

Section: Resultsmentioning

confidence: 99%

TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

Decressac

Mattsson

Weikop

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

618

615

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The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synucleininduced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.adeno-associated virus | Beclin | aggregates | synucleinopathy A major hallmark of Parkinson disease (PD) that contributes to the progressive loss of nigral dopamine (DA) neurons is α-synucleinopathy. Defects in clearance of oligomeric or misfolded proteins have been associated with aging and several neurodegenerative disorders (1-4). In human PD and related Lewy Body diseases, the presence of α-synuclein-positive (α-syn + ) aggregates is associated with accumulation of autophagosomes and reduction of lysosomal markers in affected nigral DA neurons, suggesting a defect in lysosome-mediated clearance of α-syn aggregates (5-7).How dysfunction of the autophagy-lysosome pathway (ALP) contributes to the pathogenesis of PD remains unclear. Under physiological conditions, α-syn is degraded by the ubiquitinproteasome system and the ALP, including macroautophagy and chaperone-mediated autophagy (6,(8)(9)(10)(11)(12). In cases of α-syn overload, however, misfolded or mutated α-syn fails to be processed and α-syn clearance by chaperone-mediated autophagy is blocked (12)(13)(14)(15). In this situation, processing of excess α-syn, or toxic α-syn species, will depend on the functional integrity of the macroautophagy pathway (14). In support, it has been shown that mice deficient in one of the autophagy-related (atg) proteins develop neurodegeneration, and that deficiency in atg7 or the PD-associated protein PARK9 (ATP13A2, a lysosomal ATPase) causes PD-like neurodegeneration, both in vitro and in vivo (7,(16)(17)(18)(19). In humans, PD has been genetically linked to the rare lysosomal storage diseases, Gaucher disease a...

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“…One of the underling mechanisms of cell death is oxidative stress, which has gained special attention because of its association with the reported H 2 O 2 and free radical formation, decreased superoxide dismutase (SOD) activity, increased monoaminoxidase (MAO) activity and mitochondrial complex toxicity (Martínez-Cerdeño et al 2010, Decressac et al 2012.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of Portulaca oleracea extracts against 6-hydroxydopamine-induced lesion of dopaminergic neurons

Martins

Rodrigues

Silva

et al. 2016

An. Acad. Bras. Ciênc.

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The Portulaca oleracea L. (Portulacaceae) is a cosmopolitan species with a wide range of biological activities, including antioxidant and neuroprotective actions. We investigated the effects of P. oleracea extracts in a 6-hydroxydopamine rat model of Parkinson's disease, a debilitating disorder without effective treatments. Chemical profiles of aqueous and ethanolic extracts of whole plant were analyzed by thin layer chromatography and the antioxidant activity was assessed by 2,2-diphenyl-1-picrilhidrazila method. Male Wistar rats received intrastriatal 6-hydroxydopamine and were treated with vehicle or extracts (oral, 200 and 400 mg/kg) daily for two weeks. The behavioral open field test was conducted at days 1 and 15. Immunohistochemical analysis was performed 4 weeks after surgery to quantify tyrosine-hydroxylase cell counts in the substantia nigra pars compacta. Extracts presented antioxidant activity in concentrations above 300 µg/kg. The chromatographic analysis revealed the presence of Levodopa, alkaloids, flavonoids, saponins, tannins, terpenoids and polysaccharides. Both extracts improved motor recovery 15 days after lesion and protected from tyrosine-hydroxylase cell loss after 4 weeks, but these effects were more evident for the aqueous extract. Because the dopamine precursor is present, in addition to antioxidant compounds and neuroprotective effects, P. oleracea can be considered as potential strategy for treating Parkinson's disease.

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Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease

Cited by 119 publications

References 29 publications

Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

Neuroprotective effect of Portulaca oleracea extracts against 6-hydroxydopamine-induced lesion of dopaminergic neurons

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