JURNAL DROSOPHILA MELANOGASTER PDF

geotaxis (Hi5) strains of Drosophila melanogaster (fruit fly) differ in Keywords: gene-pleiotropy; Drosophila; geotaxis; circadian; cry; Pdf; tau. During the last two decades, research using the genetically amenable fruitfly has established Drosophila melanogaster as a valuable model system in the study. Morgan et al have found 85 strain mutan of Drosophila melanogaster. The result show that the morphological of Drosophilla melanogaster wild type, sepia and plum Available at: >.

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Human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people. The majority of the diseases are associated with pathogenic oligomers from misfolded proteins, eventually causing the formation of aggregates and the progressive loss of neurons in the brain and nervous system. Several of these proteinopathies are sporadic and the cause of pathogenesis remains elusive. The limitations of human genetics, however, make it necessary to use model systems to analyse affected genes and pathways in more detail.

During the last two decades, research using the genetically amenable fruitfly has established Drosophila melanogaster as a valuable model system in the study of human neurodegeneration.

Moreover, these studies also demonstrate that the fruitfly can be used to screen chemical compounds melqnogaster their potential to prevent or ameliorate the disease, which in turn can directly guide clinical research and the development of novel therapeutic strategies for the treatment of human neurodegenerative diseases. Human neurodegenerative diseases describe a clinical condition characterised by the selective and progressive loss of neurons, eventually leading dtosophila cognitive, behavioural and physical defects that can cause the death of the patient [ 1 ].

Neurodegenerative diseases are categorised by clinical appearance and pathology, such as movement disorders e. Age is the greatest risk factor and adult-onset neurodegenerative diseases present a growing socio-economic burden for developed societies because of increased life expectancy.

Current estimates for the number of individuals suffering, for example, from AD are as drisophila as 16 million across the United States, France, Germany, Italy, Spain, United Kingdom, and Japan, and the prevalence of AD is estimated to exceed 21 million patients by [ 2 ].

For the vast majority of neurodegenerative diseases, the causes are unclear and effective treatments are lacking. At its best, prescribed treatments such as acetylcholinesterase inhibitors AD treatment [ 3 ] or levodopa PD treatment [ 4 ] provide modest symptomatic relief in a proportion of nelanogaster. To date, no drug has been identified that does more than improve symptoms. In those sporadic cases, no indication allows a decided inference about the underlying causes as well as the pathogenic mechanisms involved, apart from drosopbila as the main risk factor.

This lack of mechanistic insights has been challenged over the last two decades by two different but mutually overlapping approaches. These inclusions are characterised by protein aggregates that accumulate in the extracellular milieu or intracellular compartments drosolhila affected neurons.

The proteins are usually modified fragmented, phosphorylated, ubiquitinated and their identification provides a mechanistic link to the potential aberrant pathway mediating pathogenesis. Rdosophila is a striking mystery, however, that comparable inclusions can be observed in several diseases, such as tangles in AD and MND, although present in different neuronal cell types. This enigma as well as clinical evidence suggesting that neurodegeneration can occur even in the absence of inclusion formation continues to fuel the debate as to whether aggregate formation is a cause of disease or rather an attempt of the cell to protect itself.

In any case, the identification of the nature and content of proteinaceous inclusions alone has not revealed a major breakthrough in understanding disease formation.

Drosophila melanogaster in the Study of Human Neurodegeneration

However, in conjunction with information generated by the second approach, these data led to the identification of key pathogenic pathways operant in human neurodegeneration. Familial cases show clinical features similar to sporadic cases but at the same time are heritable, substantiating the reasonable quest to identify the origin, cause and underlying mechanisms of disease. Accordingly, large-scale pedigree analyses and genome-wide association studies have been and are still carried out in order to identify genes and loci that are affected in neurodegenerative diseases [see recent example, 1718 ].

The limitations of jurnnal genetic drossophila however, often make it difficult to analyse genes and pathways in any further detail, because of complex patterns of inheritance, lack of sufficient family pedigree data and population-based genetic heterogeneity.

These models range from yeast [ 19 ] and C. But yet, in most of the cases, these models fulfil only some of the criteria expected to apply in the study of human dtosophila. In addition, an ideal model system would provide further detailed information: An organism that meets all these criteria in a formidable jurna, is the fruitfly Drosophila melanogaster.

The protostomian, ecdysozoan arthropod Drosophila melanogaster belongs to a sub-species of the Drosophilidaedipteran insects that are found all over the globe. During the course of evolution, the arthropod lineage already separated from the vertebrate lineage more than million years ago [ 2122 ], suggesting that Drosophila might be completely unrelated to humans.

However, genetic, molecular and behavioural analyses over more than a century suggest otherwise, and Drosophila has been used as a prime model organism for experimental studies of multi-cellular eukaryotic biology. This led to the discovery of fundamental biological principles, such as validation of the chromosomal theory melanogasterr inheritance and the first experimental description of the gene as a functional unit [ 23 ]. Apart from tradition, the melangoaster for using the fruitfly as a study object are manifold: Drosophila is cheap and easy to maintain in the laboratory Fig.

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The entire Drosophila genome is encoded by roughly 13, genes as compared to 27, human genes, melanoggaster on only four pairs of chromosomes as compared to 23 pairs in human [ 29 ]. Thanks to very well-described anatomy and development [ 3031 ], and the availability of molecular genetic tools drosopgila 32 drosophilw 34 ], Drosophila is one of the most extensively used genetic model organisms to study complex biological processes.

In comparison to other organisms like C. Drosophila as a model organism in the study of age-related neurodegeneration. Their anatomy displays characteristic features such as compound eyes, wings and bristles that can be used as phenotypes to study neurodegeneration without affecting the survival of the fly.

The more rigid a diet e. These similarities to human ageing and lifespan, together with a highly conserved genetic makeup, make Drosophila a powerful model system in the study of adult-onset, age-related neurodegeneration. Adult brain of Drosophila. Note that cell bodies arrowheads are topologically separated from axonal extensions which make up mleanogaster neuropil. This allows the visualisation of cortical areas in the fly brain, including optic lobes OLantennal lobes ALsuperior protocerebrum SPlateral protocerebrum LPmushroom bodies MBdeuterocerebrum Dand subesophageal ganglion SG.

Based on this method, dopaminergic neurons can not only be monitored, drksophila also manipulated, and cell numbers as well as axonal projections can be used as phenotypic read-out parameters to study drosopbila in Drosophila.

International Journal of Evolutionary Biology

The value of Drosophila as a model system has been amply demonstrated by the fact that many genes and processes first discovered in the fly have proven to be conserved in jurnql organisms, including humans. Comparative analysis of whole genome sequencing revealed striking similarities in the structural composition of individual genes of Homo sapiens and Drosophila [ 36 ].

Moreover, the molecules and mechanisms underlying core modules of cell biology are conserved as well: These data provide compelling evidence for the structural conservation of genes due to common origin; they elucidate a deep homology underlying cell biological mechanisms that extends beyond gene structure to patterned protein expression and function. This notion is further supported by experiments demonstrating that Drosophila and human genes can substitute each other in species-specific but evolutionarily conserved mechanisms underlying brain development in insects and mammals [ 42 – 45 ].

Based on these observations, it is obvious that Drosophila can offer unique opportunities in the study of human melanobaster These features make Drosophila a prime model organism in the study of adult-onset, age-related neurodegeneration.

The fundamental aims in the study of neurodegeneration are to elucidate underlying pathogenic pathway s and in turn the development and successful application of targeted treatment s to stop dgosophila at least ameliorate the disease. The genetic dissection of disease pathways is therefore a reasonable means to address these aims and three mutually interrelated approaches are utilised in Drosophila:.

Mis-expression of a human gene is used to investigate its functional properties in a neurodegenerative process and to drosopbila its interactions drosophioa other Drosophila proteins. Most robust models have been established using nervous system-specific Gal4 drivers, thereby corresponding drosophilq the human condition. However, several other tissues are also used as a phenotypic read-out system, including the compound eyes, wings and bristles, because a degenerative phenotype can be revealed without affecting the survival of the fly.

There are, however, serious drawbacks to this approach: The latter can and should be avoided by site-specific genomic integration of the UAS construct for details, see [ 50 ] so that the same levels jkrnal protein drosoophila are achieved. In comparison to wild-type protein expression, only this will permit meaningful conclusions about the impact of mis-expressing a human mutant protein or its post-translational modifications that frequently occur in neurodegeneration, such as hyperphosphorylation or ubiquitination.

The ultimate goal is to gain insights into the drosophkla and function of a Drosophila homologue of a human disease gene. By way melanofaster homology between the fly and human protein, a reasonable inference can be made on the function of the human protein, and hypotheses and predictions can be deduced about the potential pathogenic pathway s.

A third approach jurnap utilised once a neurodegenerative phenotype is established. Drosophila offers the advantage of performing unbiased genetic screens to jjurnal enhancers and suppressors on a genome-wide basis.

Several labs have used the ease and accessibility of the compound eye to carry out such modifier screens, and targeted genes that either suppress or enhance the rough eye phenotype, thereby signifiyng the candidate genes as members of a common pathogenic pathway. However, in only very few cases [ 6266 ], the results obtained in Drosophila led to the identification of a human homologue that is similarly involved in the corresponding human disease.

The potential reason s for such a meagre yield are phenotypic screens predominantly based on eye-specific Gal4 drivers that are already active during development, thereby generating a rough eye phenotype in the newly hatched adult fly – a situation that does not mimic nor model adult-onset neurodegeneration in an age-related manner.

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A Drosophila compound screen is achieved by simply feeding flies with their usual food to which a defined concentration drosopihla the compound has been added Fig. In addition, compound screens have been ineffective when based on a rough eye phenotype that is generated during development and drossophila in the newly hatched adult fly [Luz and Hirth, unpublished].

This is because flies can be easily raised on drug-treated food but ingestion stops during puparium formation and the subsequent pupal stage, which lasts four days until the adult fly hatches. Moreover, this final stage of development is characterised by a high metabolic rate related to metamorphosis, during which a previously incorporated drug loses its efficacy.

Drug treatment in Drosophila. The applied drug is screened for its potential to either enhance or suppress a given droosophila phenotype that has been caused by targeted genetic manipulation, such as rough eyes caused by mis-expression of human tau, a movement disorder caused by dysfunction of Drosophila TDPor reduced lifespan caused by mis-expression of human ASYN. The resulting effects on locomotion are quantified using a negative geotaxis assay: A calculus then determines the melanogastef performance of these flies exposed to a given drug concentration and at a specific day.

Drosophiila graph shows that the geotaxis performance inversely correlates with drug concentration and age, suggesting that this drug enhances a movement disorder in a concentration-dependant and age-related manner. These successful cases are mainly but not only based on fly models of adult-onset, age-related neurodegeneration, and resulted in improvements relevant to human disease, including extended life-span in models of AD [ 67 ] and prolonged survival of melanogaser neurons in models of PD [ 6869 ] as well as the complete rescue of disease-related phenotypes [ 70 ].

The relevance and impact of such small-scale compound screens in Drosophila cannot be rated highly enough because of uurnal potential for translational research: Accordingly, Drosophila drug screens in cancer research [ 72 ] have already identified compounds that are now in phase I and II clinical trials, illustrating the enormous potential for its application in the study of human diseases.

The above drospohila experimental approaches have established Drosophila as an excellent model organism in the study of human neurodegeneration. Me,anogaster reviews have covered detailed aspects of this topic and are highly recommended to the reader [ 73 – 85 ]. In the following article, key and novel findings as well as their implications are summarized and reviewed. In addition, Apolipoprotein E isoform epsilon4 has been identified as a risk factor [ 88 ]. AD is characterized by progressive memory loss and the subsequent degeneration of large areas of the brain [ 8990 ].

Microscopically, AD pathology reveals neuritic plaques, composed mainly of Abeta peptides, and neurofibrillary tangles, hurnal of abnormal tau protein [ 869192 ]. Abeta peptides are produced by proteolytic cleavage of the APP transmembrane receptor at the beta and gamma sites.

Abeta42 forms protofibrils and fibrils much more readily than Abeta40 and is the predominant form of the peptide found in plaques. These data led to the amyloid cascade hypothesis as the main culprit of AD formation [ 9394 ].

Flies deleted for the Appl gene are viable, fertile, and morphologically normal, yet they exhibit subtle behavioural deficits: Interestingly, however, a recent report identified a beta-secretase-like cleavage site in APPL [ 96 ], but further proof is required to show that this is a functional site leading to Abeta-like deposition. These models recapitulate, at least to some extent, aspects of human AD pathology, including Abeta plaque deposition [ 9798 ], defective axonal transport [ 99] and axonopathies [ ], mitochondrial mislocalisation [ ], defects in synaptic plasticity [ ] and progressive locomotor deficits [ 98 ], affected life-span [ 9798], and age-dependent neurodegeneration including vacuolization of the brain [ 9798].

The severity of these phenotypes is related to Abeta toxicity, with the Abeta 42 arctic mutation being the most toxic form.

Drosophila Abeta models were subsequently utilised to target modifiers of AD pathology by genetic or pharmacological interference. Genetic experiments showed that secretase inhibitors and neprilysin can ameliorate Abeta42 phenotypes, by either reducing Abeta production [ 67, ] or by increasing Abeta degradation drospphila].

This study also showed that mutations in the copper transporter Atox1 which interacts with FKBP52 enhance Abeta pathology which can be suppressed in FKBP52 mutant flies raised on a copper chelator diet [ ]. Pharmacological interference identified Congo Red [ ] and glutaminyl cyclase inhibitors [ ] as effective suppressors of Abeta deposition and amyloid plaque formation.

Resulting from these studies, several signalling pathways have been identified as potential mediators of Abeta pathogenesis. In any case, these studies not only corroborate the amyloid cascade hypothesis, but also support recent data indicating that Abeta melangoaster, rather than plaque formation, is the toxic event that acts as a seed for Abeta aggregation [, ].

Yet, it is unknown how Abeta oligomerization causes neuronal cell death.