The Degenerating Substantia Nigra as a Susceptible Region for Gene Transfer-Mediated Inflammation

Roca, Valeria Ines; Casabona, Juan Cruz; Radice, Pablo Daniel; Murta, Verónica; Pitossi, Fernando Juan

doi:10.4061/2011/931572

Cited by 7 publications

(8 citation statements)

References 74 publications

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“…3E, Mander’s coefficient = 0.09±0.6) or GFAP-positive astrocytes (images not shown, Mander’s coefficient = 0.05±1.0). Furthermore, we did not observe an up-regulation of microglia in response to the AAV2 injections similar to other reports (Roca et al, 2011). However 6-OHDA administration increased Iba1-positive microglia on the ipsilateral side compared to the contralateral uninjected side (data not shown).…”

Section: Resultssupporting

confidence: 92%

RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells

Pranski

Dalal

Sanford

et al. 2013

Neurobiology of Disease

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Chronic activation of the NF-κB pathway is associated with progressive neurodegeneration in Parkinson’s disease (PD). Given the role of neuronal RING finger protein 11 (RNF11) as a negative regulator of the NF-κB pathway, in this report we investigated the function of RNF11 in dopaminergic cells in PD-associated neurodegeneration. We found that RNF11 knock-down in an in vitro model of PD mediated protection against 6-OHDA-induced toxicity. In converse, over-expression of RNF11 enhanced 6-OHDA-induced dopaminergic cell death. Furthermore, by directly manipulating NF-κB signaling, we showed that the observed RNF11-enhanced 6-OHDA toxicity is mediated through inhibition of NF-κB-dependent transcription of TNF-α, antioxidants GSS and SOD1, and anti-apoptotic factor BCL2. Experiments in an in vivo 6-OHDA rat model of PD recapitulated the in vitro results. In vivo targeted RNF11 over-expression in nigral neurons enhanced 6-OHDA toxicity, as evident by increased amphetamine-induced rotations and loss of nigral dopaminergic neurons as compared to controls. This enhanced toxicity was coupled with down-regulation of NF-κB transcribed GSS, SOD1, BCL2, and neurotrophic factor BDNF mRNA levels, in addition to decreased TNF-α mRNA levels in ventral mesenchephalon samples. In converse, knockdown of RNF11 was associated with protective phenotypes and increased expression of above-mentioned NF-κB transcribed genes. Collectively, our in vitro and in vivo data suggest that RNF11-mediated inhibition of NF-κB in dopaminergic cells exaggerates 6-OHDA toxicity by inhibiting neuroprotective responses while loss of RNF11 inhibition on NF-κB activity promotes neuronal survival. The decreased expression of RNF11 in surviving cortical and nigral tissue detected in PD patients, thus implies a compensatory response in the diseased brain to PD-associated insults. In summary, our findings demonstrate that RNF11 in neurons can modulate susceptibility to 6-OHDA toxicity through NF-κB mediated responses. This neuron-specific role of RNF11 in the brain has important implications for targeted therapeutics aimed at preventing neurodegeneration.

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Section: Resultssupporting

confidence: 92%

RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells

Pranski

Dalal

Sanford

et al. 2013

Neurobiology of Disease

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“…This vision was wrong. Microglial activation can lead to toxic but also protective effects on the on-going neurodegenerating neurons of the SN (reviewed in Roca et al, 2011). This review will be focused on the functional consequences of two prototypical microglial-derived cytokines [IL-1β and TNF-α] on PD physiopathology.…”

Section: Parkinson’s Disease and Neuroinflammationmentioning

confidence: 99%

“…The activation of microglial cells in the degenerating SN in PD is ubiquitous. It has been found in mice, rats, and monkeys models of PD based on neurotoxins such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) pesticides such as rotenone or alpha-synuclein overexpression (reviewed in Roca et al, 2011). In addition, robust microglial activation has been found in the SN in post-mortem samples and by imaging techniques in PD patients (reviewed in Roca et al, 2011).…”

Section: Pd and Microglial Activationmentioning

confidence: 99%

“…The neuroimmunology of the brain parenchyma differs in many aspects from the immune response elicit systemically (for extensive review see Lowenstein and Castro, 2003; Perry et al, 2010; Roca et al, 2011). In relation with the interaction between IL-1β and TNF-α, the cytokine network in the brain parenchyma differs from the periphery.…”

Section: Interactions Between Il-1β and Tnf-αmentioning

confidence: 99%

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Interleukin-1β and tumor necrosis factor-α: reliable targets for protective therapies in Parkinson’s Disease?

Leal

Casabona

Puntel

et al. 2013

Front. Cell. Neurosci.

142

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Neuroinflammation has received increased attention as a target for putative neuroprotective therapies in Parkinson’s Disease (PD). Two prototypic pro-inflammatory cytokines interleukin-1β (IL-1) and tumor necrosis factor-α (TNF) have been implicated as main effectors of the functional consequences of neuroinflammation on neurodegeneration in PD models. In this review, we describe that the functional interaction between these cytokines in the brain differs from the periphery (e.g., their expression is not induced by each other) and present data showing predominantly a toxic effect of these cytokines when expressed at high doses and for a sustained period of time in the substantia nigra pars compacta (SN). In addition, we highlight opposite evidence showing protective effects of these two main cytokines when conditions of duration, amount of expression or state of activation of the target or neighboring cells are changed. Furthermore, we discuss these results in the frame of previous disappointing results from anti-TNF-α clinical trials against Multiple Sclerosis, another neurodegenerative disease with a clear neuroinflammatory component. In conclusion, we hypothesize that the available evidence suggests that the duration and dose of IL-1β or TNF-α expression is crucial to predict their functional effect on the SN. Since these parameters are not amenable for measurement in the SN of PD patients, we call for an in-depth analysis to identify downstream mediators that could be common to the toxic (and not the protective) effects of these cytokines in the SN. This strategy could spare the possible neuroprotective effect of these cytokines operative in the patient at the time of treatment, increasing the probability of efficacy in a clinical setting. Alternatively, receptor-specific agonists or antagonists could also provide a way to circumvent undesired effects of general anti-inflammatory or specific anti-IL-1β or TNF-α therapies against PD.

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“…Neuroinflammation is one of the immune processes of paramount importance in PD ( Wang et al, 2015 ). Reactive microglia increased significantly in the substantia nigra region of PD patients upon post-mortem examinations ( McGeer et al, 1988 ; Roca et al, 2011 ). Moreover, enhanced microglial activation was also observed in various PD animal models, including α-synuclein overexpression models, as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA) and rotenone neurotoxin-induced mice, rats and monkeys ( Roca et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting the inflammasome in Parkinson’s disease

Goh

et al. 2022

Front. Aging Neurosci.

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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in which neuroinflammation plays pivotal roles. An important mechanism of neuroinflammation is the NLRP3 inflammasome activation that has been implicated in PD pathogenesis. In this perspective, we will discuss the relationship of some key PD-associated proteins including α-synuclein and Parkin and their contribution to inflammasome activation. We will also review promising inhibitors of NLRP3 inflammasome pathway that have potential as novel PD therapeutics. Finally, we will provide a summary of current and potential in vitro and in vivo models that are available for therapeutic discovery and development.

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The Degenerating Substantia Nigra as a Susceptible Region for Gene Transfer-Mediated Inflammation

Cited by 7 publications

References 74 publications

RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells

RING finger protein 11 (RNF11) modulates susceptibility to 6-OHDA-induced nigral degeneration and behavioral deficits through NF-κB signaling in dopaminergic cells

Interleukin-1β and tumor necrosis factor-α: reliable targets for protective therapies in Parkinson’s Disease?

Targeting the inflammasome in Parkinson’s disease

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