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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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Adult brain of Drosophila. (a) Confocal image of a parafin cross-section through the adult Drosophila head; auto-immunofluorescence visualises theommatidia of the compound eye (CE), the optic lobe (OL) and the central brain (CB). Note that cell bodies (arrowheads) are topologically separated fromaxonal extensions which make up the neuropil. (b) Confocal image of a whole mount adult brain immunolabelled with anti-nc82 which recognises theBruchpilot protein that is specifically enriched in active zones of synaptic terminals. This allows the visualisation of cortical areas in the fly brain, includingoptic lobes (OL), antennal lobes (AL), superior protocerebrum (SP), lateral protocerebrum (LP), mushroom bodies (MB), deuterocerebrum (D), andsubesophageal ganglion (SG). (c) Optical cross-section of a whole-mount adult brain of a transgenic Drosophila immunolabeled with anti-nc82; tyrosinehydroxylase (TH)-specific Gal4 drives UAS-mCD8:GFP expression, a membrane-tagged GFP (TH>mGFP). Because TH is the rate-limiting enzyme ofdopamine synthesis, this transgenic Gal4/UAS combination visualises dopaminergic neurons and their axonal extensions (white/light grey). Based on thismethod, dopaminergic neurons can not only be monitored, but also manipulated, and cell numbers as well as axonal projections can be used as phenotypicread-out parameters to study parkinsonism in Drosophila. Scale bar: 50 µm.
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Figure 2: Adult brain of Drosophila. (a) Confocal image of a parafin cross-section through the adult Drosophila head; auto-immunofluorescence visualises theommatidia of the compound eye (CE), the optic lobe (OL) and the central brain (CB). Note that cell bodies (arrowheads) are topologically separated fromaxonal extensions which make up the neuropil. (b) Confocal image of a whole mount adult brain immunolabelled with anti-nc82 which recognises theBruchpilot protein that is specifically enriched in active zones of synaptic terminals. This allows the visualisation of cortical areas in the fly brain, includingoptic lobes (OL), antennal lobes (AL), superior protocerebrum (SP), lateral protocerebrum (LP), mushroom bodies (MB), deuterocerebrum (D), andsubesophageal ganglion (SG). (c) Optical cross-section of a whole-mount adult brain of a transgenic Drosophila immunolabeled with anti-nc82; tyrosinehydroxylase (TH)-specific Gal4 drives UAS-mCD8:GFP expression, a membrane-tagged GFP (TH>mGFP). Because TH is the rate-limiting enzyme ofdopamine synthesis, this transgenic Gal4/UAS combination visualises dopaminergic neurons and their axonal extensions (white/light grey). Based on thismethod, dopaminergic neurons can not only be monitored, but also manipulated, and cell numbers as well as axonal projections can be used as phenotypicread-out parameters to study parkinsonism in Drosophila. Scale bar: 50 µm.

Mentions: Apart from tradition, the reasons for using the fruitfly as a study object are manifold: Drosophila is cheap and easy to maintain in the laboratory (Fig. 1a); it can give rise to a large number of genetically identical progeny; it has a rather short life span ranging from 40 to 120 days (Fig. 1b) depending on diet and stress [24, 25]; it shows complex behaviour, including learning and memory [26, 27], driven by a sophisticated brain (Fig. 2) and nervous system [28]. The entire Drosophila genome is encoded by roughly 13,600 genes as compared to 27,000 human genes, located on only four pairs of chromosomes as compared to 23 pairs in human [29]. Thanks to very well-described anatomy and development [30, 31], and the availability of molecular genetic tools [32-34], Drosophila is one of the most extensively used genetic model organisms to study complex biological processes. In comparison to other organisms like C. elegans and the mouse, the fly provides a very powerful genetic model system for the analysis of brain and behavioural disorders related to human disease: its brain is complex enough (as compared to C. elegans) to make fly behaviour highly interesting and relevant to humans but it is still small enough (as compared to mouse) for an in-depth structural and functional analysis [35].


Drosophila melanogaster in the study of human neurodegeneration.

Hirth F - CNS Neurol Disord Drug Targets (2010)

Adult brain of Drosophila. (a) Confocal image of a parafin cross-section through the adult Drosophila head; auto-immunofluorescence visualises theommatidia of the compound eye (CE), the optic lobe (OL) and the central brain (CB). Note that cell bodies (arrowheads) are topologically separated fromaxonal extensions which make up the neuropil. (b) Confocal image of a whole mount adult brain immunolabelled with anti-nc82 which recognises theBruchpilot protein that is specifically enriched in active zones of synaptic terminals. This allows the visualisation of cortical areas in the fly brain, includingoptic lobes (OL), antennal lobes (AL), superior protocerebrum (SP), lateral protocerebrum (LP), mushroom bodies (MB), deuterocerebrum (D), andsubesophageal ganglion (SG). (c) Optical cross-section of a whole-mount adult brain of a transgenic Drosophila immunolabeled with anti-nc82; tyrosinehydroxylase (TH)-specific Gal4 drives UAS-mCD8:GFP expression, a membrane-tagged GFP (TH>mGFP). Because TH is the rate-limiting enzyme ofdopamine synthesis, this transgenic Gal4/UAS combination visualises dopaminergic neurons and their axonal extensions (white/light grey). Based on thismethod, dopaminergic neurons can not only be monitored, but also manipulated, and cell numbers as well as axonal projections can be used as phenotypicread-out parameters to study parkinsonism in Drosophila. Scale bar: 50 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Adult brain of Drosophila. (a) Confocal image of a parafin cross-section through the adult Drosophila head; auto-immunofluorescence visualises theommatidia of the compound eye (CE), the optic lobe (OL) and the central brain (CB). Note that cell bodies (arrowheads) are topologically separated fromaxonal extensions which make up the neuropil. (b) Confocal image of a whole mount adult brain immunolabelled with anti-nc82 which recognises theBruchpilot protein that is specifically enriched in active zones of synaptic terminals. This allows the visualisation of cortical areas in the fly brain, includingoptic lobes (OL), antennal lobes (AL), superior protocerebrum (SP), lateral protocerebrum (LP), mushroom bodies (MB), deuterocerebrum (D), andsubesophageal ganglion (SG). (c) Optical cross-section of a whole-mount adult brain of a transgenic Drosophila immunolabeled with anti-nc82; tyrosinehydroxylase (TH)-specific Gal4 drives UAS-mCD8:GFP expression, a membrane-tagged GFP (TH>mGFP). Because TH is the rate-limiting enzyme ofdopamine synthesis, this transgenic Gal4/UAS combination visualises dopaminergic neurons and their axonal extensions (white/light grey). Based on thismethod, dopaminergic neurons can not only be monitored, but also manipulated, and cell numbers as well as axonal projections can be used as phenotypicread-out parameters to study parkinsonism in Drosophila. Scale bar: 50 µm.
Mentions: Apart from tradition, the reasons for using the fruitfly as a study object are manifold: Drosophila is cheap and easy to maintain in the laboratory (Fig. 1a); it can give rise to a large number of genetically identical progeny; it has a rather short life span ranging from 40 to 120 days (Fig. 1b) depending on diet and stress [24, 25]; it shows complex behaviour, including learning and memory [26, 27], driven by a sophisticated brain (Fig. 2) and nervous system [28]. The entire Drosophila genome is encoded by roughly 13,600 genes as compared to 27,000 human genes, located on only four pairs of chromosomes as compared to 23 pairs in human [29]. Thanks to very well-described anatomy and development [30, 31], and the availability of molecular genetic tools [32-34], Drosophila is one of the most extensively used genetic model organisms to study complex biological processes. In comparison to other organisms like C. elegans and the mouse, the fly provides a very powerful genetic model system for the analysis of brain and behavioural disorders related to human disease: its brain is complex enough (as compared to C. elegans) to make fly behaviour highly interesting and relevant to humans but it is still small enough (as compared to mouse) for an in-depth structural and functional analysis [35].

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