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Engrailed homeoprotein protects mesencephalic dopaminergic neurons from oxidative stress

ABSTRACT: Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks and protects dopaminergic neurons against apoptosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE72321 | GEO | 2015/09/24

SECONDARY ACCESSION(S): PRJNA293745

REPOSITORIES: GEO

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Engrailed homeoprotein protects mesencephalic dopaminergic neurons from oxidative stress

Project description:Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks and protects dopaminergic neurons against apoptosis. RNA-seq data for differentially expressed genes in the SNpc of En1+/- mice, En2 infused mice and 6-OHDA/En2 injection experiments.

2015-09-24 | E-GEOD-72321 | biostudies-arrayexpress

Mus musculus

Project description:Engrailed homeoprotein protects mesencephalic dopaminergic neurons from oxidative stress

| PRJNA293745 | ENA

Single Cell Transcriptomics of iPSC derived neurons under genetic and toxic stressors

Project description:Human iPSC derived dopaminergic neurons were characterized using unbiased single cell transcriptomics. Then study the genetic effect of the A-syn A53T mutation along with oxidative and ER stress induced by rotenone and tunicamycin respectively.

2020-05-29 | E-MTAB-9154 | biostudies-arrayexpress

Cell-penetrant SELENOT mimetic protects dopaminergic neurons and ameliorates motor function

Project description:Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction for which there is an unmet need for better treatment options. Although oxidative stress is a common feature of neurodegenerative diseases, notably PD, there is currently no efficient therapeutic strategy able to tackle this system-wide pathophysiological process. Based on our previous observations of the potent antioxidant and neuroprotective activity of SELENOT, a vital thioredoxin-like selenoprotein, we designed the small peptide PSELT from its redox active site in order to determine its potential polyfunctional activity in PD models. PSELT proved to site in order to be protective for neurotoxin-treated dopaminergic neurons and fibers against oxidative stress determine its potential polyfunctional activity in PD models. PSELT proved to be protective for neurotoxin-treated dopaminergic neurons and fibers against oxidative stress and cell death. We demonstrate that PSELT is cell-permeable and acts in different subcellular compartments of dopaminergic neurons where oxidative stress exerts its deleterious effects. This protective activity prevented neurodegeneration and restored phosphorylated tyrosine hydroxylase levels, leading to improved motor skills in rodent models of PD

2021-02-08 | GSE151808 | GEO

The Cellular and Genomic Response of Dopaminergic Neurons (N27) to Commericial “Capped” Nanosilver

Project description:Global gene expression indicated that N27 neurons exposed to each nanoAg material (1.0 ppm, 18 hr) responded primarily to PVP coated nanoAg of both sizes with affected pathways largely associated with mitochondrial dysfunction (PVP 75 nm nanoAg) and Nrf-2 mediated oxidative stress (PVP 10 nm nanoAg) pathways. N27 rat dopaminergic neurons were exposed to non-cytoxic (0.5-5.0 ppm) concentrations of nanoAg of different sizes (10 nm, 75 nm) and “cappings” (PVP, citrate).

2013-06-20 | E-GEOD-48087 | biostudies-arrayexpress

Nigral Transcriptomic Profiles in Engrailed-1 Hemizygous Mouse Models of Parkinson’s Disease Reveal Upregulation of Oxidative Phosphorylation-Related Genes Associated with Resistance to Dopaminergic Neurodegeneration

Project description:Engrailed 1 (EN1) is a conserved transcription factor essential for programming, survival, and maintenance of midbrain dopaminergic neurons. En1-hemizygosity (En1+/-) leads to a spontaneous Parkinson’s disease-like (PD-like) progressive nigrostriatal degeneration as well as motor impairment and depressive-like behavior in SwissOF1 (OF1-En1+/-) mice. This phenotype is absent in C57Bl/6j (C57-En1+/-) mice. Here we studied PD-like phenotypes and early transcriptome profiles in OF1 wild-type (WT) and OF1-En1+/- male mice and compare to that of C57 WT and C57-En1+/- male mice. To detect transcriptional changes prior to dopaminergic cell loss, we performed RNA-seq of 1-week old mice substantia nigra pars compacta (SNpc). Histology and stereology were used to assess dopaminergic nigrostriatal pathology in 4 and 16 weeks old mice. OF1-En1+/- mice showed an increase (79%) in dopaminergic striatal axonal swellings from 4 to 16 weeks and a loss (23%) of dopaminergic neurons in the SNpc at 16 weeks compared to OF1 WT. Axonal swellings were also present in C57-En1+/- mice but did not increase over time. 52 differentially expressed genes (DEGs) were observed between the C57-WT and the C57-En1+/- mice, while 198 DEGs were observed in the OF1 strain. Enrichment analysis revealed that the neuroprotective phenotype of C57-En1+/- mice was associated with an upregulation of oxidative phosphorylation-related genes compared to both C57 WT and to OF1- En1+/- mice. These results highlight the importance of considering genetic background in PD models and provide valuable insight on how expression of mitochondrial proteins before the onset of neurodegeneration is associated to vulnerability of nigrostriatal dopaminergic neurons.

2024-01-24 | GSE236461 | GEO

Drosophila Embryos: Control Wild Type vs. Engrailed GooseberryNeuro double heterozygous

Project description:Transcriptional profiling of drosophila embryos (0-14h collection) comparing control wild type embryos with embryos double heterozygous for Engrailed and GooseberryNeuro Two conditions experiment, Wild Type vs. Double heterezygous Engrailed GooseberryNeuro. Biological replicates: 3 control, 3 mutant conditions, independently selected. Triplicate per array

2014-01-01 | E-GEOD-46628 | biostudies-arrayexpress

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration

Project description:Circadian rhythm dysfunction is a hallmark of Parkinson Disease (PD), and diminished expression of the core clock gene Bmal1 has been described in PD patients. BMAL1 is required for core circadian clock function, but also serves non-rhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and can exacerbate dopaminergic neurodegeneration in response to MPTP. Here we examined the impact of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, post-natal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase-positive (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not due to disruption of behavioral circadian rhythms, and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Finally, global Bmal1 deletion exacerbated TH+ neuron loss following injection of alpha-synclein fibrils. Transcriptomic analysis of neuron-specific Bmal1 KO brain revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson Disease.

2023-08-18 | GSE241200 | GEO

Drosophila Embryos: Engrailed GooseberryNeuro double heterozygous vs Control Wild Type

Project description:Transcriptional profiling of drosophila embryos (0-14h collection) comparing embryos double heterozygous for Engrailed and GooseberryNeuro with control wild type embryos

2014-01-01 | GSE46628 | GEO

Loss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis

Project description:Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.

2021-07-26 | GSE179228 | GEO

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