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Necrosis, apoptosis, necroptosis, three modes of action of dopaminergic neuron neurotoxins.

ABSTRACT: Most of the Parkinson's disease (PD) cases are sporadic, although several genes are directly related to PD. Several pathways are central in PD pathogenesis: protein aggregation linked to proteasomal impairments, mitochondrial dysfunctions and impairment in dopamine (DA) release. Here we studied the close crossing of mitochondrial dysfunction and aggregation of ?-synuclein (?-syn) and in the extension in the dopaminergic neuronal death. Here, using rat primary cultures of mesencephalic neurons, we induced the mitochondrial impairments using "DA-toxins" (MPP+, 6OHDA, rotenone). We showed that the DA-Toxins induced dopaminergic cell death through different pathways: caspase-dependent cell death for 6OHDA; MPP+ stimulated caspase-independent cell death, and rotenone activated both pathways. In addition, a decrease in energy production and/or a development of oxidative stress were observed and were linked to ?-syn aggregation with generation of Lewy body-like inclusions (found inside and outside the dopaminergic neurons). We demonstrated that any of induced mitochondrial disturbances and processes of death led to ?-syn protein aggregation and finally to cell death. Our study depicts the cell death mechanisms taking place in in vitro models of Parkinson's disease and how mitochondrial dysfunctions is at the cross road of the pathologies of this disease.

SUBMITTER: Callizot N

PROVIDER: S-EPMC6483187 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Programmed cell death, including apoptosis, mitochondria-mediated necrosis, and necroptosis, is critically involved in ischemic cardiac injury, pathological cardiac remodeling, and heart failure progression. Whereas apoptosis and mitochondria-mediated necrosis signaling is well established, the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure remain elusive. METHODS:We examined the role of tumor necrosis factor receptor-associated factor 2 (Traf2) in regulating myocardial necroptosis and remodeling using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which Traf2 regulates necroptosis signaling. RESULTS:We identified a critical role for Traf2 in myocardial survival and homeostasis by suppressing necroptosis. Cardiac-specific deletion of Traf2 in mice triggered necroptotic cardiac cell death, pathological remodeling, and heart failure. Plasma tumor necrosis factor ? level was significantly elevated in Traf2-deficient mice, and genetic ablation of TNFR1 largely abrogated pathological cardiac remodeling and dysfunction associated with Traf2 deletion. Mechanistically, Traf2 critically regulates receptor-interacting proteins 1 and 3 and mixed lineage kinase domain-like protein necroptotic signaling with the adaptor protein tumor necrosis factor receptor-associated protein with death domain as an upstream regulator and transforming growth factor ?-activated kinase 1 as a downstream effector. It is important to note that genetic deletion of RIP3 largely rescued the cardiac phenotype triggered by Traf2 deletion, validating a critical role of necroptosis in regulating pathological remodeling and heart failure propensity. CONCLUSIONS:These results identify an important Traf2-mediated, NF?B-independent, prosurvival pathway in the heart by suppressing necroptotic signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure.

Project description:To date, there is no good evidence that intestine epithelial cells (IEC) affected by ischemia/reperfusion (I/R) injury are able to cause cortical neuron injury directly. Additionally, it remains unclear whether the neuronal damage caused by I/R injured IEC can be affected by therapeutic hypothermia (TH, 32 °C). To address these questions, we performed an oxygen-glucose deprivation (OGD) affected IEC-6-primary cortical neuron coculture system under normothermia (37 °C) or TH (32 °C) conditions. It was found that OGD caused hyperpermeability in IEC-6 cell monolayers. OGD-preconditioned IEC-6 cells caused cortical neuronal death (e.g., decreased cell viability), synaptotoxicity, and neuronal apoptosis (evidenced by increased caspase-3 expression and the number of TUNEL-positive cells), necroptosis (evidenced by increased receptor-interacting serine/threonine-protein kinase-1 [RIPK1], RIPK3 and mixed lineage kinase domain-like pseudokinase [MLKL] expression), and pyroptosis (evidenced by an increase in caspase-1, gasdermin D [GSDMD], IL-1?, IL-18, the apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], and nucleotide oligomerization domain [NOD]-like receptor [NLRP]-1 expression). TH did not affect the intestinal epithelial hyperpermeability but did attenuate OGD-induced neuronal death and synaptotoxicity. We also performed quantitative real-time PCR to quantify the genes encoding 84 exosomal microRNAs in the medium of the control-IEC-6, the control-neuron, the OGD-IEC-6 at 37 °C, the OGD-IEC-6 at 32 °C, the neuron cocultured with OGD-IEC-6 at 37 °C, and the neurons cocultured with OGD-IEC-6 at 32 °C. We found that the control IEC-6 cell s or cortical neurons are able to secrete a basal level of exosomal miRNAs in their medium. OGD significantly up-regulated the basal level of each parameter for IEC-6 cells. As compared to those of the OGD-IEC-6 cells or the control neurons, the OGD-IEC-6 cocultured neurons had significantly higher levels of 19 exosomal miRNAs related to apoptosis, necroptosis, and/or pyroptosis events. Our results identify that I/R injured intestinal epithelium cells can induce cortical neuron death via releasing paracrine mediators such as exosomal miRNAs associated with apoptosis, necroptosis, and/or pyroptosis, which can be counteracted by TH.

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Necrosis, apoptosis, necroptosis, three modes of action of dopaminergic neuron neurotoxins.

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