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Drosophila melanogaster in the study of human neurodegeneration.

Hirth F - CNS Neurol Disord Drug Targets (2010)

Bottom Line: 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.Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression.As a result of these studies, several signalling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone morphogenetic protein (BMP) signalling, have been shown to be deregulated in models of proteinopathies, suggesting that two or more initiating events may trigger disease formation in an age-related manner.

View Article: PubMed Central - PubMed

Affiliation: King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, Department of Neuroscience, London, UK. Frank.Hirth@kcl.ac.uk

ABSTRACT
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. Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression. 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. These studies offer reliable models for Alzheimer's, Parkinson's, and motor neuron diseases, as well as models for trinucleotide repeat expansion diseases, including ataxias and Huntington's disease. As a result of these studies, several signalling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone morphogenetic protein (BMP) signalling, have been shown to be deregulated in models of proteinopathies, suggesting that two or more initiating events may trigger disease formation in an age-related manner. Moreover, these studies also demonstrate that the fruitfly can be used to screen chemical compounds for 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.

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Related in: MedlinePlus

Drug treatment in Drosophila. (a) Four vials with flies are kept on cornmeal food each of which has been supplemented with a differentconcentration of the same drug. The applied drug is screened for its potential to either enhance or suppress a given neurodegeneration phenotype that has beencaused by targeted genetic manipulation, such as rough eyes caused by mis-expression of human tau, a movement disorder caused by dysfunction ofDrosophila TDP-43, or reduced lifespan caused by mis-expression of human ASYN. In this way, Drosophila models of neurodegeneration can be used toscreen compound collections for their potential to prevent or ameliorate a specific neurodegenerative “disease”. (b) Three different concentrations of a drug(10 µM, 100 µM, and 1 mM) are chronically applied to ageing Drosophila, as compared to vehicle treated flies. The resulting effects on locomotion arequantified using a negative geotaxis assay: flies are shaken to the bottom of a vial/cylinder; their innate behaviour triggers them to move upwards (againstgeotaxis) and the time it takes them to reach the top is scored for a cohort of flies and multiple replicates. A calculus then determines the relative performanceof these flies exposed to a given drug concentration and at a specific day. The graph shows that the geotaxis performance inversely correlates with drugconcentration and age, suggesting that this drug enhances a movement disorder in a concentration-dependant and age-related manner.
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Figure 3: Drug treatment in Drosophila. (a) Four vials with flies are kept on cornmeal food each of which has been supplemented with a differentconcentration of the same drug. The applied drug is screened for its potential to either enhance or suppress a given neurodegeneration phenotype that has beencaused by targeted genetic manipulation, such as rough eyes caused by mis-expression of human tau, a movement disorder caused by dysfunction ofDrosophila TDP-43, or reduced lifespan caused by mis-expression of human ASYN. In this way, Drosophila models of neurodegeneration can be used toscreen compound collections for their potential to prevent or ameliorate a specific neurodegenerative “disease”. (b) Three different concentrations of a drug(10 µM, 100 µM, and 1 mM) are chronically applied to ageing Drosophila, as compared to vehicle treated flies. The resulting effects on locomotion arequantified using a negative geotaxis assay: flies are shaken to the bottom of a vial/cylinder; their innate behaviour triggers them to move upwards (againstgeotaxis) and the time it takes them to reach the top is scored for a cohort of flies and multiple replicates. A calculus then determines the relative performanceof these flies exposed to a given drug concentration and at a specific day. The graph shows that the geotaxis performance inversely correlates with drugconcentration and age, suggesting that this drug enhances a movement disorder in a concentration-dependant and age-related manner.

Mentions: In addition to these genetic approaches, a fourth one uses established fly models of neurodegeneration in order to screen compound collections for their potential to prevent or ameliorate the “disease”. A Drosophila compound screen is achieved by simply feeding flies with their usual food to which a defined concentration of the compound has been added (Fig. 3). There are obvious drawbacks to such screens, especially when used for adult onset, age-related neurodegeneration phenotypes, as these screens are time-consuming and far from being “high-throughput”. In addition, compound screens have been ineffective when based on a rough eye phenotype that is generated during development and detectable 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.


Drosophila melanogaster in the study of human neurodegeneration.

Hirth F - CNS Neurol Disord Drug Targets (2010)

Drug treatment in Drosophila. (a) Four vials with flies are kept on cornmeal food each of which has been supplemented with a differentconcentration of the same drug. The applied drug is screened for its potential to either enhance or suppress a given neurodegeneration phenotype that has beencaused by targeted genetic manipulation, such as rough eyes caused by mis-expression of human tau, a movement disorder caused by dysfunction ofDrosophila TDP-43, or reduced lifespan caused by mis-expression of human ASYN. In this way, Drosophila models of neurodegeneration can be used toscreen compound collections for their potential to prevent or ameliorate a specific neurodegenerative “disease”. (b) Three different concentrations of a drug(10 µM, 100 µM, and 1 mM) are chronically applied to ageing Drosophila, as compared to vehicle treated flies. The resulting effects on locomotion arequantified using a negative geotaxis assay: flies are shaken to the bottom of a vial/cylinder; their innate behaviour triggers them to move upwards (againstgeotaxis) and the time it takes them to reach the top is scored for a cohort of flies and multiple replicates. A calculus then determines the relative performanceof these flies exposed to a given drug concentration and at a specific day. The graph shows that the geotaxis performance inversely correlates with drugconcentration and age, suggesting that this drug enhances a movement disorder in a concentration-dependant and age-related manner.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992341&req=5

Figure 3: Drug treatment in Drosophila. (a) Four vials with flies are kept on cornmeal food each of which has been supplemented with a differentconcentration of the same drug. The applied drug is screened for its potential to either enhance or suppress a given neurodegeneration phenotype that has beencaused by targeted genetic manipulation, such as rough eyes caused by mis-expression of human tau, a movement disorder caused by dysfunction ofDrosophila TDP-43, or reduced lifespan caused by mis-expression of human ASYN. In this way, Drosophila models of neurodegeneration can be used toscreen compound collections for their potential to prevent or ameliorate a specific neurodegenerative “disease”. (b) Three different concentrations of a drug(10 µM, 100 µM, and 1 mM) are chronically applied to ageing Drosophila, as compared to vehicle treated flies. The resulting effects on locomotion arequantified using a negative geotaxis assay: flies are shaken to the bottom of a vial/cylinder; their innate behaviour triggers them to move upwards (againstgeotaxis) and the time it takes them to reach the top is scored for a cohort of flies and multiple replicates. A calculus then determines the relative performanceof these flies exposed to a given drug concentration and at a specific day. The graph shows that the geotaxis performance inversely correlates with drugconcentration and age, suggesting that this drug enhances a movement disorder in a concentration-dependant and age-related manner.
Mentions: In addition to these genetic approaches, a fourth one uses established fly models of neurodegeneration in order to screen compound collections for their potential to prevent or ameliorate the “disease”. A Drosophila compound screen is achieved by simply feeding flies with their usual food to which a defined concentration of the compound has been added (Fig. 3). There are obvious drawbacks to such screens, especially when used for adult onset, age-related neurodegeneration phenotypes, as these screens are time-consuming and far from being “high-throughput”. In addition, compound screens have been ineffective when based on a rough eye phenotype that is generated during development and detectable 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.

Bottom Line: 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.Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression.As a result of these studies, several signalling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone morphogenetic protein (BMP) signalling, have been shown to be deregulated in models of proteinopathies, suggesting that two or more initiating events may trigger disease formation in an age-related manner.

View Article: PubMed Central - PubMed

Affiliation: King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, Department of Neuroscience, London, UK. Frank.Hirth@kcl.ac.uk

ABSTRACT
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. Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression. 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. These studies offer reliable models for Alzheimer's, Parkinson's, and motor neuron diseases, as well as models for trinucleotide repeat expansion diseases, including ataxias and Huntington's disease. As a result of these studies, several signalling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone morphogenetic protein (BMP) signalling, have been shown to be deregulated in models of proteinopathies, suggesting that two or more initiating events may trigger disease formation in an age-related manner. Moreover, these studies also demonstrate that the fruitfly can be used to screen chemical compounds for 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.

Show MeSH
Related in: MedlinePlus