Identification of novel modifiers of Aβ toxicity by transcriptomic analysis in the fruitfly

Favrin, Giorgio; Bean, Daniel; Bilsland, Elizabeth; Boyer, Hélène; Fischer, Bettina; Russell, Steven; Crowther, Damian C.; Baylis, H. A.; Oliver, Stephen G.; Giannakou, Maria E.

doi:10.1038/srep03512

Cited by 21 publications

(25 citation statements)

References 40 publications

(65 reference statements)

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“…Interestingly, Aβ42 activated the Toll signaling pathway, suggesting that Toll, a pattern recognition receptor (PPR), recognizes the structure of Aβ42 aggregates as a danger-associated molecular pattern (DAMP), which explains the potent inflammatory response in AD brains (Salminen et al, 2009). More recently, the Crowther lab used a transcriptomic approach to identify the mechanisms mediating Aβ42 toxicity (Favrin et al, 2013). The microarrays identified genes involved in normal aging, including oxidative stress, immune response, and protein secretion, due to high levels of Aβ42 that altered gene expression in the young flies.…”

Section: Drosophila Models Of Aβ42 Neurotoxicitymentioning

confidence: 99%

Modeling the complex pathology of Alzheimer's disease in Drosophila

Fernández-Fúnez

Mena

Rincón-Limas

2015

Experimental Neurology

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Alzheimer’s disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of Amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncovering the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42.

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Section: Drosophila Models Of Aβ42 Neurotoxicitymentioning

confidence: 99%

Modeling the complex pathology of Alzheimer's disease in Drosophila

Fernández-Fúnez

Mena

Rincón-Limas

2015

Experimental Neurology

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“…This, together with the similarity in exon arrangement between Sod3 in Drosophila and Sod4 in C. elegans , suggests that SOD3v1 is a secreted extracellular protein, whereas SOD3v2 is membrane associated. Further evidence suggesting the two forms are functionally different is seen in the results of Favrin [ 22 ] who found that the long form RD/RE transcripts are over 10-fold more highly expressed in a Drosophila Alzheimer's model, whereas expression of the short form, RA/RB, falls off with ageing similar to the control.…”

Section: Discussionmentioning

confidence: 99%

“…The gene has since been confirmed as an extracellular SOD in a parasitic wasp [ 20 ] and in Drosophila [ 21 ]. It was also identified as one of the genes with a significant change in expression in a Drosophila model of Alzheimer's disease [ 22 ]. In mammals, extracellular SOD is highly expressed in the lung, testis, central nervous system and circulatory system [ 23 , 24 ] and is medically important through its involvement in cardiovascular disease [ 8 , 25 ] and age-related cognitive decline [ 2 , 12 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Cloning and expression analysis of Drosophila extracellular Cu Zn superoxide dismutase

et al. 2014

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In the present study, we cloned and sequenced the mRNAs of the Sod3 [extracellular Cu Zn SOD (superoxide dismutase)] gene in Drosophila and identified two mRNA products formed by alternative splicing. These products code for a long and short protein derived from the four transcripts found in global expression studies (Flybase numbers Dmel\CG9027, FBgn0033631). Both mRNA process variants contain an extracellular signalling sequence, a region of high homology to the Sod1 (cytoplasmic Cu Zn SOD) including a conserved AUG start, with the longer form also containing a hydrophobic tail. The two fully processed transcripts are homologous to Caenorhabditis elegans Sod3 mRNA showing the same processing pattern. Using an established KG p-element+ insertion line (KG06029), we demonstrate that the Sod3 codes for an active Cu Zn SOD. We found differing expression patterns across sex with higher levels of expression of Sod3 in females. There is a correlation of Sod1 and Sod3 gene expression and activity that can explain why Sod3 was not seen in earlier studies of Sod1. Finally, we found no effect on lifespan with the Sod3 hypomorph mutation (Sod3KG06029) but did observe a significant increase in resistance to paraquat and H2O2 (hydrogen peroxide).

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“…Sod3 was also found to be induced in flies over-expressing the human Alzheimer's disease protein fragment Abeta, and to negatively affect survival of the mutant flies (Favrin et al 2013). …”

Section: Reduced Sod Function and Agingmentioning

confidence: 95%

Superoxide Dismutase (SOD) Genes and Aging in Drosophila

Tower

2015

Life Extension

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Since their discovery by McCord and Fridovich the superoxide dismutase (SOD) enzymes have been of particular interest to the field of aging. The Drosophila SOD genes are required for normal oxidative stress resistance and life span, and have been targets for investigation of mechanisms of aging. The ability of SOD genes to affect Drosophila life span is dependent upon the genetic background, including the sex of the animal, as well as the dietary environment. There is increasing understanding of the role of the SODs in signaling pathways that modulate aging. The Cu/ZnSOD is important in linking diet to life span, and MnSOD can activate the mitochondrial unfolded protein response and increase life span. The SOD genes also modulate survival in Drosophila models of human disease. The conservation of SOD genes and functions in Drosophila combined with the availability of powerful genetic and transgenic technologies promises to keep Drosophila at the forefront of research on aging and the role of SOD.

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Identification of novel modifiers of Aβ toxicity by transcriptomic analysis in the fruitfly

Cited by 21 publications

References 40 publications

Modeling the complex pathology of Alzheimer's disease in Drosophila

Modeling the complex pathology of Alzheimer's disease in Drosophila

Cloning and expression analysis of Drosophila extracellular Cu Zn superoxide dismutase

Superoxide Dismutase (SOD) Genes and Aging in Drosophila

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