Drosophila Models For Tau Toxicity
Insoluble aggregates of the MT-associated protein Tau are a common feature of so-called tauopathies like frontotemporal dementia with parkinsonism linked to chromosome 17 , progressive supranuclear palsy and Picks disease and others . Central feature of tauopathies is the presence of paired helical filaments, which assemble into intracellular neurofibrillary tangles in affected tissues . Several disease-linked mutations in the Tau gene affect correct splicing of its MT binding sites, thus enhancing abnormal phosphorylation and detachment of the protein. Both steps are believed to be crucial in the process of forming paired helical filaments and higher order neurofibrillary tangles .
Table 2 Overview of performed large-scale screens for modifiers of toxicity induced by expression of AD-linked genes inDrosophila melanogaster
In addition, Iijima-Ando et al. generated another phosphorylation-resistant Tau variant TauS262A. Retinal coexpression of wild-type human Tau and DNA damage-activated checkpoint kinase 2 resulted in enhancement of the REP. In contrast, coexpression of Chk2 and TauS262A had no effect on eye surface integrity .
Fruit Flies’ Brains Studied To Help Crack Dementia
The humble fruit fly could help scientists unlock the secrets of Alzheimer’s disease.
A new £20m Dementia Research Institute at Cardiff University includes a fly laboratory.
Researchers will be studying the brains of the flies because they share a large proportion of their genes with humans.
They also have a £1m microscope to hand, which is able to carry out thousands of tests on cells and collect data automatically.
In Wales, there are 45,000 people living with dementia but this is set to increase to 100,000 by 2055.
Cardiff is part of a new £290m network of dementia research centres, which includes Cambridge, Edinburgh and London, looking to find a cure.
The fruit fly has a part to play because it has many genes which are similar to those in Alzheimer’s disease in humans.
Its brain – roughly the size of a poppy seed – contains about 100,000 neurons human brains have 100 billion.
But only having a life cycle of a few months, scientists can track how the fly’s brain ages far more quickly.
Dr Owen Peters, a lecturer and one of the researchers, said the flies can help us understand brain function.
“Flies allow us to do imaging techniques which we aren’t able to do in other model systems,” he said.
“If we find a gene in the human genetic studies that looks like it’s linked to Alzheimer’s disease – and flies have it – it allows us to have a very rapid, inexpensive system, which we can test to see how these affect brain function.”
Concluding Remarks And Future Perspectives
AD, like many of the common neurodegenerative diseases, shows a high degree of heritability indeed 60-80% of the risk in so-called sporadic AD is genetic . The existing human genetics studies, however, have explained only half of this risk. The main contributions are from the apolipoprotein E and clusterin loci , and to a lesser extent from PICALM, CR1 and SORL1. The heritability that remains unaccounted likely stems from a large number of genes, each of which provides a small contribution to disease risk. The current generation of genome-wide association studies are designed to detect these small contributions by exhaustively linking single nucleotide polymorphisms with risk for disease across hundreds of thousands of loci per individual .
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A Team Of Scientists From Cambridge And Sweden Have Discovered A Molecule That Can Prevent A Toxic Protein Involved Alzheimer’s Disease From Building Up In The Brain
When we examined these flies we found that the Affibody not only prevented and reversed the formation of A clumps, it also promoted clearance of the toxic A clumps from the flies’ brains.
Dr Leila Luheshi
They found that in test tube studies the molecule not only prevents the protein from forming clumps but can also reverse this process. Then, using fruit flies with Alzheimer& rsquo s disease, they showed that the same molecule effectively & ldquo cures& rdquo the insects of the disease.
Alzheimer’s disease is the most common neurodegenerative disorder and is linked to the misfolding and aggregation of a small protein known as the amyloid peptide. Previous studies in animal models have shown that aggregation of A damages neurones causing memory impairment and cognitive deficits similar to those seen in patients with Alzheimer’s disease. The mechanisms underlying this damage are, however, still not understood.
The new molecule – designed by scientists in Sweden – is a small protein known as an Affibody . In this new study, researchers at the University of Cambridge and the Swedish University of Agricultural Sciences found that in test-tube experiments this protein binds to the A peptide, preventing it from forming clumps and breaking up any clumps already present.
In a second experiment, they studied the effect of this Affibody in a Drosophila model of Alzheimer’s disease previously developed at Cambridge.
The study is published today in PLoS Biology.
Drosophila As A Model Organism For Ad
Animal model systems are used to study specific functional aspects of human diseases in general and neurodegenerative diseases in particular. AD models range from yeast and Caenorhabditis elegans to mammals and human cell culture systems . However, no model system combines easy use and essential criteria of AD, like cognitive and behavioral dysfunction caused by cell type-specific neurodegeneration, cellular pathophysiology including aggregate formation, clear pattern of inheritance and genetic homogeneity. Although vertebrate model organisms reflect pathologic hallmarks of human diseases very well, these model organisms have the disadvantage of care, time and cost-intensive handling. Using comparable short-lived model organisms allows fast data acquisition facilitating large-scale experiments, although these organisms might lack some pathophysiological characteristics of AD .
Table 1 Advantages and disadvantages of usingDrosophilaas a model organism for neurodegenerative diseases like AD
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Why Fruit Flies Are A Good Genetic Model For Human Disease Study
by Mohit Kumar Jolly, The Conversation
If you have a Facebook account, you are likely to have seen someone pour an ice bucket on themselves in the name of raising awareness for amyotropic lateral sclerosis . ALS is a disease that affects nerve cells in the brain, and it falls into a class of diseases known as neurodegenerative, which include diseases such as Parkinson’s, Alzheimer’s and Huntington’s. All of them are incurable and claim many lives around the world. These diseases can be caused by genetic mutations, but our understanding of what causes these remains poor.
A study, conducted by Manish Jaiswal and colleagues and led by Hugo Bellen and Michael Wangler at the Baylor College of Medicine, just published in Cell, takes a key step forward. They identified hundreds of new mutations in specific genes that are associated with various aspects of the development, function and maintenance of neural system in the fruit fly Drosophila melanogaster. The fruit fly is a stand-in for humans, and allows investigation of the molecular mechanisms of 26 human diseases, including ALS.
Researchers could use Drosophila melanogaster, because it is a well-established model organism to understand the molecular mechanisms of many human diseases. This is because: about 75% of human disease-causing genes are found in the fly in a similar form, it is easy to work with and breeds quickly, and many tools are available to manipulate any genes in it.
Messing with a fruit fly
Genetic shortcut
Genetic Treatment Extends Fruit Fly Lifespan And Prevents Alzheimers Damage
25 February 2021
Modifying brain cell activity can extend the lifespan of fruit flies while also preventing the damage characteristic of Alzheimers disease, finds a new study led by UCL researchers.
The researchers found that by modifying the levels of two different proteins that are active in two different types of brain cells, they could extend fruit fly lifespans by around 7-9% , they report in PNAS.
The treatments also reduced the buildup of amyloid, the harmful brain proteins characteristic of Alzheimers disease, in flies that have been bred as models for researching the disease.
The research group at the UCL Institute of Healthy Ageing has previously found other ways to extend fruit fly lifespan by over 10%, or even by 48% when using a combination of three drugs .* While smaller than the lifespan extensions in some other fruit fly studies, this latest research is notable for extending lifespan by only targeting one type of cell in the nervous system, rather than cells across the whole body. They have yet to investigate whether combining their new treatments with other methods could yield additional benefits.
In the latest study, the researchers were investigating ways to modify the insulin growth factor signalling pathway, which is being increasingly studied for its key role in the ageing process.
Here, we were seeking to understand how ageing predisposes the brain to dementia, in order to one day find new ways to help us live well for longer.
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Screening For Genetic Modifiers Of Human Tau Toxicity
Screening for modifiers of the over-expression of human tau in fly models has been carried out by several groups. The most widely used phenotype in such screens is the rough eye that results from the retinal expression of wild type and variants of human tau. As the rough appearance is visible as soon as the adult fly hatches, this phenotype has been adopted widely as a surrogate marker of tau neurotoxicity.
The screen performed by Blard and colleagues identified a tyrosine phosphatase as a modifier of tau toxicity however phosphorylation status was not a major functional group. Indeed, this disparity between screens is remarkable. Blard speculated that this might be due to differences in the screening protocol, because in their hands, over-expression of the candidate kinases par-1 and GSK-3 yielded a rough eye phenotype, and so would have been excluded from their analysis. The Blard screen instead emphasised the importance of cytoskeletal components. In particular, cheerio, the fly orthologue of the actin-binding protein filamin, was identified as an enhancer of tau pathology, in agreement with the findings of Shulman and Feany . They also showed that tau over-expression causes morphological abnormalities in larval neuromuscular end plates which can be rescued or enhanced by the modifiers in the screen. This finding is of particular interest because there is mounting evidence that synaptic dysfunction is one of the earliest pathological events in AD .
Genetic Treatment Extends Fruit Fly Lifespan And Prevents Alzheimer’s Damage
Modifying brain cell activity can extend the lifespan of fruit flies while also preventing the damage characteristic of Alzheimer’s disease, finds a new study led by UCL researchers.
The researchers found that by modifying the levels of two different proteins that are active in two different types of brain cells, they could extend fruit fly lifespans by around 7-9% , they report in PNAS.
The treatments also reduced the buildup of amyloid, the harmful brain proteins characteristic of Alzheimer’s disease, in flies that have been bred as models for researching the disease.
The research group at the UCL Institute of Healthy Aging has previously found other ways to extend fruit fly lifespan by over 10%, or even by 48% when using a combination of three drugs . While smaller than the lifespan extensions in some other fruit fly studies, this latest research is notable for extending lifespan by only targeting one type of cell in the nervous system, rather than cells across the whole body. They have yet to investigate whether combining their new treatments with other methods could yield additional benefits.
In the latest study, the researchers were investigating ways to modify the insulin growth factor signaling pathway, which is being increasingly studied for its key role in the aging process.
“Here, we were seeking to understand how aging predisposes the brain to dementia, in order to one day find new ways to help us live well for longer.”
Citation
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Fruit Flies And Alzheimer’s Disease
A Catalyst article about the use of fruit flies in research about genetic diseases and in particular the study of DNA and how genes can cause disease. Scientists have studied the effects of placing new DNA into the chromosomes of fruit flies. One line of research is to utilise fruit flies with the human gene involved in Alzheimers disease. This assists scientists, as they try to work out better treatments for genetic diseases.
This article is from Catalyst: GCSE Science Review 2006, Volume 17, Issue 2.
Catalyst is a science magazine for students aged 14-19 years. Annual subscriptions to print copies of the magazine can be purchased from Mindsets.
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About This Genetics Research News
Abstract
Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system
Reduced activity of insulin/insulin-like growth factor signaling increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors are required however, distinct TFs are likely responsible for these effects in different tissues.
Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila. Starting from published single-cell transcriptomic data, we report that forkhead is endogenously expressed in neurons, whereas forkhead-box-O is expressed in glial cells.
Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimers disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan.
Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.
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Exercise Induced Effects In A Fly Model Of Alzheimers Disease
To address, whether gently induced physical activity can alter phenotypes of human A42-expressing fruit flies, the DAM System in combination with a rotating tube device were used to monitor AD flies undergoing activity induction. After a training protocol consisting of daily exercise over the entire life span of the animals was found to be detrimental for AD flies a protocol of 12 consecutive days of 30 min exercise was designed. Oregon-R wild type flies, elav-GAL4 driver strain and UAS-A42/+ reporter strain were used as controls. Non-exercising flies did not show relevant activity during siesta sleep at time ZT7 when exercise units were given .
Exercising AD flies survived significantly longer than non-exercising AD flies and showed a similar life span compared to elav-GAL4 and UAS-A42/+ control flies. Survival rates of control groups were not affected by undergoing the identical exercise protocol . Oregon-R wild type flies displayed the longest life span of all tested groups .
Twelve days of consecutive activity induction did not affect overall sleep or short term sleep quantity in Oregon-R strain and UAS-A42 control group . Exercising elav-GAL4 flies showed elevated levels of sleep over the entire experiment and more fragmented sleep in the post-exercise phase .
Advancing Alzheimers Research Through The Lifespan Of A Fruit Fly
McWhorter School of Pharmacy faculty Patty Jumbo-Lucioni uses fruit fly models to study the bodys renin-angiotensin system and the anti-hypertension drugs that actively silence the RAS.
The average lifespan of a fruit fly is roughly 40 to 45 days. Fruit flies age quickly, said Patty Jumbo-Lucioni, assistant professor in McWhorter School of Pharmacy. In three weeks, you can have a very compromised, aging fly, especially if it has the Alzheimers disease genes.
Jumbo-Lucioni has worked with fruit fly models for the majority of her career, yet her interest in Alzheimers disease has developed more recently. After completing her postdoctoral training in the field of neuroscience, she knew she wanted her research to focus on the brain utilizing fruit fly models.
At its foundation, her research revolves around the bodys renin-angiotensin system , which controls blood pressure, and the anti-hypertension drugs that actively silence the RAS. Over time, research has shown that an overactive renin-angiotensin system can not only cause high blood pressure, but it may also be associated with the way we age, she said.
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Screening For Genetic Modifiers Of A Peptide Toxicity
Notably, both screens identified a role for the transition metals copper and iron . Rival and colleagues used an Affymetrix® chip analysis to measure changes in gene expression in response to A and reported that oxidative stress was a particularly significant contributor . The most powerful modifying genes were those encoding iron-binding proteins of particular note were the heavy and light chains of ferritin. Co-expression of ferritin heavy chain and A suppressed the longevity and behavioural phenotypes and reduced oxidative damage despite an increased accumulation of A in the brain. A molecular dissection of the oxidative stress pathway highlighted the pathogenic role of the Fenton reaction in generating hydroxyl radicals. The ability of A to induce a Toll/NFB-dependent inflammatory response probably also increases the oxidative stress experienced by neurones .
Researchers Use Fruit Flies To Unlock Mysteries Of Human Diabetes
by Stanford University Medical Center
For the first time, the tiny fruit fly can be used to study how mutations associated with the development of diabetes affect the production and secretion of the vital hormone insulin.
The advance is due to a new technique devised by researchers at the Stanford University School of Medicine that allows scientists to measure insulin levels in the insects with extremely high sensitivity and reproducibility.
The experimental model is likely to transform the field of diabetes research by bringing the staggering power of fruit fly genetics, honed over 100 years of research, to bear on the devastating condition that affects millions of Americans. Until now, scientists wishing to study the effect of specific mutations on insulin had to rely on the laborious, lengthy and expensive genetic engineering of laboratory mice or other mammals.
In contrast, tiny, short-lived fruit flies can be bred in dizzying combinations by the tens of thousands in just days or weeks in small flasks on a laboratory bench.
“I normally avoid the term, but I think Dr. Park’s new technique is a true breakthrough,” said Seung Kim, MD, PhD, professor of developmental biology. “Only in selected mammals can researchers measure insulin with this degree of sensitivity.”
The power of a tiny model system
Understanding the effect of each mutation
Tip of the iceberg
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