Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration in<i>Drosophila melanogaster</i>

Ambegaokar, Surendra S.; Jackson, George R.

doi:10.1534/genetics.110.119545

Cited by 28 publications

(30 citation statements)

References 62 publications

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“…In addition, white and rosy , two modifiers of tau toxicity identified earlier from this study (61), also are important in lipid trafficking. The gene rosy regulates lipid droplet coupling to the plasma membrane during lipid secretion (244), and the mammalian homolog of white —ABCG1—is a major effector in lipid trafficking (245).…”

Section: Discussionsupporting

confidence: 60%

Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

Ambegaokar

Jackson

2011

Human Molecular Genetics

105

133

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A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ∼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-β and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3β is strongly upregulated due to TDP-43 expression, and reduced GSK-3β dosage is also a common suppressor of Aβ42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation.

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Section: Discussionsupporting

confidence: 60%

Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

Ambegaokar

Jackson

2011

Human Molecular Genetics

105

133

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“…We established Drosophila as a model for CIPN primarily utilizing one common wild-type strain, Oregon-R. 21 However, Drosophila mutants and transgenic flies are produced using a variety of genetic background strains, and many of these strains are known to exhibit different behaviors or altered sensitivity to neurodegeneration. 24 In addition, because DRG from multiple rodent strains have different sensitivity to cisplatin, 25 it was necessary to understand the effect of genetic background on Drosophila sensitivity to cisplatin. We first compared three Drosophila strains commonly used as wild-type or background controls: Oregon-R, Canton-S, and w 1118 .…”

Section: Drosophila Wild-type Strains Have Different Sensitivity To Cmentioning

confidence: 99%

Drosophila strain specific response to cisplatin neurotoxicity

Groen

Podratz

Treb

et al. 2018

Fly

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Drosophila melanogaster has recently been developed as a simple, in vivo, genetic model of chemotherapy-induced peripheral neuropathy. Flies treated with the chemotherapy agent cisplatin display both a neurodegenerative phenotype and cell death in rapidly dividing follicles, mimicking the cell specific responses seen in humans. Cisplatin induces climbing deficiencies and loss of fertility in a dose dependent manner. Drosophila sensitivity to cisplatin in both cell types is affected by genetic background. We show that mutation or RNAi-based knockdown of genes known to be associated with CIPN incidence in humans affect sensitivity of flies to CIPN. Drosophila is a promising model with which to study the effect of genetics on sensitivity to CIPN. ARTICLE HISTORY

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“…It is important to clarify the role of these PrP C variants in the mechanism of PrP C into PrP Sc conversion in order to understand their role in prion formation. This was performed in order to exclude the potential contribution of pigment-associated effects on neuronal integrity and survival [48] in subsequent experiments that involved exposure of flies to exogenous prions. A diagrammatic representation of the VRQ PrP variants expressed in Drosophila is shown in Figure 1.…”

Section: Generation Of Ovine Prp Transgenic Drosophilamentioning

confidence: 99%

Prion-induced and spontaneous formation of transmissible toxicity in PrP transgenic Drosophila

Thackray

Zhang

et al. 2014

Biochemical Journal

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Prion diseases are fatal transmissible neurodegenerative diseases of various mammalian species. Central to these conditions is the conversion of the normal host prion protein PrP(C) into the abnormal prion conformer PrP(Sc). Mature PrP(C) is attached to the plasma membrane by a glycosylphosphatidylinositol anchor, whereas during biosynthesis and metabolism cytosolic and secreted forms of the protein may arise. The role of topological PrP(C) variants in the mechanism of prion formation and prion-induced neurotoxicity during prion disease remains undefined. In the present study we investigated whether Drosophila transgenic for ovine PrP targeted to the plasma membrane, to the cytosol or for secretion, could produce transmissible toxicity following exposure to exogenous ovine prions. Although all three topological variants of PrP were efficiently expressed in Drosophila, cytosolic PrP was conformationally distinct and required denaturation before recognition by immunobiochemical methods. Adult Drosophila transgenic for pan neuronally expressed ovine PrP targeted to the plasma membrane, to the cytosol or for secretion exhibited a decreased locomotor activity after exposure at the larval stage to ovine prions. Proteinase K-resistant PrP(Sc) was detected by protein misfolding cyclic amplification in prion-exposed Drosophila transgenic for membrane-targeted PrP. Significantly, head homogenate from all three variants of prion-exposed PrP transgenic Drosophila induced a decreased locomotor activity when transmitted to PrP recipient flies. Drosophila transgenic for PrP targeted for secretion exhibited a spontaneous locomotor defect in the absence of prion exposure that was transmissible in PrP transgenic flies. Our data are consistent with the formation of transmissible prions in PrP transgenic Drosophila.

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Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

Cited by 28 publications

References 62 publications

Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

Drosophila strain specific response to cisplatin neurotoxicity

Prion-induced and spontaneous formation of transmissible toxicity in PrP transgenic Drosophila

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