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Low molecular weight polysialic acid prevents lipopolysaccharide-induced inflammatory dopaminergic neurodegeneration in humanized SIGLEC11 transgenic mice

ABSTRACT: Low molecular weight polysialic acid prevents lipopolysaccharide-induced inflammatory dopaminergic neurodegeneration in humanized SIGLEC11 transgenic mice

PROVIDER: PRJNA717252 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14070000.fastq.gz	Fastqsanger.gz
	SRR14070001.fastq.gz	Fastqsanger.gz
	SRR14070002.fastq.gz	Fastqsanger.gz
	SRR14070003.fastq.gz	Fastqsanger.gz
	SRR14070004.fastq.gz	Fastqsanger.gz

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Low molecular weight polysialic acid prevents lipopolysaccharide-induced inflammatory dopaminergic neurodegeneration in humanized SIGLEC11 transgenic mice

Project description:Here, we investigated the effect of low molecular weight polysialic acid (polySia avDP20) on inflammatory neurodegeneration. SIGLEC11 transgenic and wild type control (WT) mice were treated intraperitoneally daily over four consecutive days with 1 µg/gbw/day LPS in conjunction with 10 μg/gbw polySia avDP20. Repeated LPS injections led to inflammation and neuronal loss in the brains of WT and SIGLEC11 transgenic mice. Transcriptome analysis by RNA-seq of total brain tissue indicated that treatment with polySia avDP20 prevented the LPS-induced upregulation of genes belonging to inflammation, TLR signaling, phagocytosis, and complement-related pathways in SIGLEC11 transgenic but not wild type mice.

2021-12-23 | GSE169637 | GEO

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Project description:Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinson’s disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients Using Ribotag technology, from mouse ventral midbrain lysates, we isolated actively translated mRNA species from control and Transferrin receptor 1-null dopaminergic neurons. Two mouse ages were used 3 wks (early neurodegeration) 10 wks (late neurodegeneration)

2015-03-11 | E-GEOD-66730 | biostudies-arrayexpress

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

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Repeated systemic challenge with lipopolysaccharides induces dopaminergic neurodegeneration in the brain by activation of the complement-phagosome pathway

Project description:Systemic inflammatory reactions mediated by chronic infections activate microglia in the central nervous system (CNS) and have been postulated to exacerbate neurodegenerative diseases. We now demonstrate in vivo that repeated systemic challenge of mice with bacterial lipopolysaccharides (LPS) maintains an elevated microglial inflammatory response and triggers neurodegeneration. Repeated chronic intraperitoneal application of LPS over four consecutive days induced loss of dopaminergic neurons in the substantia nigra, a process that was accompanied by decreased levels of dopamine in the striatum. In contrast, total cumulative LPS dose given intraperitoneally within a single acute application did not induce a decrease in dopamine levels nor neurodegeneration. Mice that received repeated systemic LPS application showed increased microglial activation, elevated production of proinflammatory cytokines and activation of the classical complement and its associated phagosome pathway in the brain. Loss of dopaminergic neurons induced by repeated systemic LPS application was rescued in complement C3 deficient mice, confirming an involvement of the complement system in neurodegeneration. Thus, our data demonstrate that repeated systemic exposure to bacterial LPS induces a microglial phagosomal inflammatory response, leading to complement-dependent damage of dopaminergic neurons.

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Effect of fyn kinase driven inflammatory cytokine associated dopaminergic neurodegeneration and microglia activation in zebrafish.

Project description:The Alzheimer's Disease and Parkinson's Disease risk locus Fyn kinase is implicated in protein pathophysiology and NF-κB microglia inflammatory signaling. To investigate in vivo mechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging we demonstrate neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Gene expression analyses reveal reduction in neuroprotective genes, and elevated inflammatory cytokines Il-1β, IL-12 and TNF-α and genes associated with oxidative stress. These phenotypes correlate with microglia activation in the larval brain. Chemical inhibition demonstrates dopaminergic neuron loss is dependent on Fyn and NF-κB/Caspase 1 signaling. We identify Stat3 activation as a novel downstream effector of Fyn signaling that acts synergistically with NF-κB in dopaminergic neuron degeneration. These results show Fyn drives neurodegeneration through NF-κB inflammatory signaling and Stat3 pathways. Activation of Stat3 provides a potential link from Fyn to mitochondrial dysfunction associated with dopaminergic neuron loss.

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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

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Project description:Systemic RNA interference-defective (SID) genes modulate dopaminergic neurodegeneration in C. elegans

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

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

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Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy

Project description:To gain insight into the role of human APOE on tau-associated neurodegeneration, we examined P301S mutant tau transgenic mice carrying humanized APOE alleles

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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.

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