Systemic RNA interference-defective (SID) genes modulate dopaminergic neurodegeneration in C. elegans
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ABSTRACT:
PROVIDER: PRJNA843950 | ENA |
REPOSITORIES: ENA
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Project description:The fine-tuning of gene expression is critical for all cellular processes; aberrations in this activity can lead to pathology, and conversely, resilience. As their role in coordinating organismal responses to both internal and external factors have increasingly come into focus, small non-coding RNAs have emerged as an essential component to disease etiology. Using Systemic RNA interference Defective (SID) mutants of the nematode Caenorhabditis elegans, deficient in gene silencing, we examined the potential consequences of dysfunctional epigenomic regulation in the context of Parkinson's disease (PD). Specifically, the loss of either the sid-1 or sid-3 genes, which encode a dsRNA transporter and an endocytic regulatory non-receptor tyrosine kinase, respectively, conferred neuroprotection to dopaminergic (DA) neurons in an established transgenic C. elegans strain wherein overexpression of human α-synuclein (α-syn) from a chromosomally integrated multicopy transgene causes neurodegeneration. We further show that knockout of a specific microRNA, mir-2, attenuates α-syn neurotoxicity; suggesting that the native targets of mir-2-dependent gene silencing represent putative neuroprotective modulators. In support of this, we demonstrated that RNAi knockdown of multiple mir-2 targets enhanced α-syn-induced DA neurodegeneration. Moreover, we demonstrate that mir-2 overexpression originating in the intestine can induce neurodegeneration of DA neurons, an effect that was reversed by pharmacological inhibition of SID-3 activity. Interestingly, sid-1 mutants retained mir-2-induced enhancement of neurodegeneration. Transcriptomic analysis of α-syn animals with and without a sid-1 mutation revealed 27 differentially expressed genes with human orthologs related to a variety of diseases, including PD. Among these was pgp-8, encoding a P-glycoprotein-related ABC transporter. Notably, sid-1; pgp-8 double mutants abolished the neurodegeneration resulting from intestinal mir-2 overexpression. This research positions known regulators of small RNA-dependent gene silencing within a framework that facilitates mechanistic evaluation of epigenetic responses to exogenous and endogenous factors influencing DA neurodegeneration, revealing a path toward new targets for therapeutic intervention of PD.
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Project description:To investigate mutations in genes involved in the cellular import of dsRNA neuroprotection, we generated a profile of individual genes affected when dsRNA transport is incapacitated and established a foundation for the systemic analysis of their distinct contributions to neuroprotection. We then identified a set of previously unreported neuroprotective proteins using data obtained from RNA-seq.
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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
2015-03-11 | GSE66730 | GEO
Project description:Using distinct mutant strains deficient in key aspects of gene silencing machinery, we provide evidence that neuroprotection appears to stem from dsRNAs that originate from the bacteria themselves, and Systemic RNA Interference Defective (SID) mutants deficient in dsRNA-mediated gene silencing do not allow for neuroprotection from the bacteria. Transcriptomic analysis between worms reared on OP50 and HB101 E. coli for multiple generations in an a-syn background revealed that the primary cellular processes involved in neuroprotection of this nature included but were not limited to endopeptidase activity, transcriptional regulation, calcium ion binding activity, and water channel activity.
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Project description:Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells. MDA-MB-231 cells were treated with scrambled SID control, 2.5µM SID peptide or untreated for 24h. Sub-confluent cultures of MDA-MB-231 cells were treated with scrambled SID control, 2.5µM SID peptide or untreated for 24h. Experiments were performed as three independent replicates.
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Project description:Targeted interference of sin3a-tgif1 function by SID decoy treatment inhibits WNT signaling and invasion in triple negative breast cancer cells. MDA-MB-231 cells were treated with scrambled SID control, 2.5µM SID peptide or untreated for 24h.
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