Chronic and progressive Parkinson's disease <scp>MPTP</scp> model in adult and aged mice

Muñoz-Manchado, Ana B.; Villadiego, Javier; Romo-Madero, Sonia; Suárez-Luna, Nela; Bermejo-Navas, Alfonso; Rodríguez‐Gómez, José A.; Garrido‐Gil, Pablo; Labandeira-Garcı́a, José Luis; Echevarría, Miriam; López‐Barneo, José; Toledo‐Aral, Juan José

doi:10.1111/jnc.13409

Cited by 76 publications

(75 citation statements)

References 71 publications

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“…Though Ndufs4 cKO mice have a significant decline (approximately 35% in the striatum) of dopamine content compared to control littermates, this decline was not sufficient to cause motor dysfunction. This is consistent with the literature that much more serve loss of striatal dopamine is required before motor deficits appears in rodents62636465666768. For example, mice exposed to MPTP can lose up to 50% of dopamine without apparent motor deficits6768.…”

Section: Discussionsupporting

confidence: 91%

“…This is consistent with the literature that much more serve loss of striatal dopamine is required before motor deficits appears in rodents62636465666768. For example, mice exposed to MPTP can lose up to 50% of dopamine without apparent motor deficits6768. Similarly, up to 80% of striatal dopamine is already lost at the onset of Parkinson’s disease diagnosis69.…”

Section: Discussionsupporting

confidence: 90%

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Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

Choi¹,

Kim²,

Tronche³

et al. 2017

Sci Rep

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Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson’s disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson’s disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons (Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson’s disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson’s disease and reduces dopamine content in the absence of dopamine neuron loss.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

Choi¹,

Kim²,

Tronche³

et al. 2017

Sci Rep

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“…Time points were selected in accordance to previously published data that demonstrate the most suitable time point to detect the onset of the neurodegenerative and neuroinflammatory processes (Virgone-Carlotta et al, 2013; Muñoz-Manchado et al, 2016). …”

Section: Methodsmentioning

confidence: 99%

Influence of Estrogen Modulation on Glia Activation in a Murine Model of Parkinson's Disease

et al. 2017

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Epidemiological data suggest a sexual dimorphism in Parkinson disease (PD), with women showing lower risk of developing PD. Vulnerability of the nigrostriatal pathway may be influenced by exposure to estrogenic stimulation throughout fertile life. To further address this issue, we analyzed the progression of nigrostriatal damage, microglia and astrocyte activation and microglia polarization triggered by intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in male, female and ovariectomized (OVX) mice, as well as in OVX mice supplemented with 17βestradiol (OVX+E). Animals were sacrificed at different time points following 6-OHDA injection and brain sections containing striatum and substantia nigra pars compacta (SNc) underwent immunohistochemistry for tyrosine hydroxylase (TH) (dopaminergic marker), immunofluorescence for IBA1 and GFAP (markers of microglia and astrocyte activation, respectively) and triple immunoflorescent to identify polarization of microglia toward the cytotoxic M1 (DAPI/IBA1/TNFα) or cytoprotective M2 (DAPI/IBA1/CD206) phenotype. SNc damage induced by 6-OHDA was significantly higher in OVX mice, as compared to all other experimental groups, at 7 and 14 days after surgery. Astrocyte activation was higher in OVX mice with respect the other experimental groups, at all time points. Microglial activation in the SNc was detected at earlier time points in male, female and OVX+E, while in OVX mice was detected at all time-points. Microglia polarization toward the M2, but not the M1, phenotype was detected in female and OVX+E mice, while the M1 phenotype was observed only in male and OVX mice. Our results support the protective effects of estrogens against nigrostriatal degeneration, suggesting that such effects may be mediated by an interaction with microglia, which tend to polarize preferentially toward an M2, cytoprotective phenotype in the presence of intense estrogenic stimulation.

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“…There is also evidence that MPTP (and its active component MPP+) activates microglia. [166] In general, the damage produced by MPTP is acute, however, there is some further progression of neurodegeneration later, even in human cases, and in all cases, the neuropathological damage perfectly resembles that seen in human cases of sporadic PD. [131]…”

Section: Part IImentioning

confidence: 99%

Parkinson's disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration

Blaylock¹

2017

Surg Neurol Int

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Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic. More recent studies have concluded that inflammation plays a central role in the disorder and that the characteristic findings can be accounted for by either mutation or oxidative damage to alpha-synuclein, with resulting immune reactions from surrounding microglia, astrocytes, and macrophages. What has been all but ignored in most of these studies is the role played by excitotoxicity and that the two processes are intimately linked, with inflammation triggered cell signaling enhancing the excitotoxic cascade. Further, there is growing evidence that it is the excitotoxic reactions that actually cause the neurodegeneration. I have coined the name immunoexcitotoxicity to describe this link between inflammation and excitotoxicity. It appears that the two processes are rarely, if ever, separated in neurodegenerative diseases.

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Chronic and progressive Parkinson's disease MPTP model in adult and aged mice

Cited by 76 publications

References 71 publications

Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

Influence of Estrogen Modulation on Glia Activation in a Murine Model of Parkinson's Disease

Parkinson's disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration

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