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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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Experimental study of Drosophila locomotor behaviour. (a) An adult wild-type fly (wt, arrow) is kept in an arena which can be a converted petridish. The fly’s activity and movement is recorded with a high-speed video camera and a computer programme tracks the resulting trajectory during a giventime-window (30sec). (b) 3min movement trajectory of a wt fly; (c) 3min trajectory of a mutant fly (ko) revealing motor deficits. Video-assisted movementtracking records locomotor behaviour and in turn allows the quantification of parameters that can be used to describe it, including walking activity, velocity,and distance travelled. By applying this method to Drosophila models of neurodegeneration, it is possible to mimic adult-onset neurodegenerative movementdisorders including Parkinson’s disease, trinucleotide repeat expansion diseases, and motor neuron diseases, and to monitor their effect on neural circuits andbehaviour, which in turn allows genetic dissection of the underlying pathogenic mechanism(s).
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Figure 4: Experimental study of Drosophila locomotor behaviour. (a) An adult wild-type fly (wt, arrow) is kept in an arena which can be a converted petridish. The fly’s activity and movement is recorded with a high-speed video camera and a computer programme tracks the resulting trajectory during a giventime-window (30sec). (b) 3min movement trajectory of a wt fly; (c) 3min trajectory of a mutant fly (ko) revealing motor deficits. Video-assisted movementtracking records locomotor behaviour and in turn allows the quantification of parameters that can be used to describe it, including walking activity, velocity,and distance travelled. By applying this method to Drosophila models of neurodegeneration, it is possible to mimic adult-onset neurodegenerative movementdisorders including Parkinson’s disease, trinucleotide repeat expansion diseases, and motor neuron diseases, and to monitor their effect on neural circuits andbehaviour, which in turn allows genetic dissection of the underlying pathogenic mechanism(s).

Mentions: To date, there is no effective therapy or cure for MND. As is the case for AD and PD, the majority of MND cases are sporadic and the causes are unknown. However, the identification of protein aggregates (fragmented, phosphorylated, ubiquitinated) in intracellular inclusions as well as the analyses of heritable, familial cases led to the identification of genes involved in MND pathogenesis (Table 4). In some cases motor neuron death is caused by mutations in a single gene, such as survival of motor neurons (SMN) causing SMA [255]. For the majority of these disease-related genes, Drosophila homologues are present (Table 4) and movement disorders can be easily monitored in the fly (Fig. 4). Thus, loss- and gain-of-function analyses or mis-expression of the human disease gene have been used to establish fly models of MND.


Drosophila melanogaster in the study of human neurodegeneration.

Hirth F - CNS Neurol Disord Drug Targets (2010)

Experimental study of Drosophila locomotor behaviour. (a) An adult wild-type fly (wt, arrow) is kept in an arena which can be a converted petridish. The fly’s activity and movement is recorded with a high-speed video camera and a computer programme tracks the resulting trajectory during a giventime-window (30sec). (b) 3min movement trajectory of a wt fly; (c) 3min trajectory of a mutant fly (ko) revealing motor deficits. Video-assisted movementtracking records locomotor behaviour and in turn allows the quantification of parameters that can be used to describe it, including walking activity, velocity,and distance travelled. By applying this method to Drosophila models of neurodegeneration, it is possible to mimic adult-onset neurodegenerative movementdisorders including Parkinson’s disease, trinucleotide repeat expansion diseases, and motor neuron diseases, and to monitor their effect on neural circuits andbehaviour, which in turn allows genetic dissection of the underlying pathogenic mechanism(s).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Experimental study of Drosophila locomotor behaviour. (a) An adult wild-type fly (wt, arrow) is kept in an arena which can be a converted petridish. The fly’s activity and movement is recorded with a high-speed video camera and a computer programme tracks the resulting trajectory during a giventime-window (30sec). (b) 3min movement trajectory of a wt fly; (c) 3min trajectory of a mutant fly (ko) revealing motor deficits. Video-assisted movementtracking records locomotor behaviour and in turn allows the quantification of parameters that can be used to describe it, including walking activity, velocity,and distance travelled. By applying this method to Drosophila models of neurodegeneration, it is possible to mimic adult-onset neurodegenerative movementdisorders including Parkinson’s disease, trinucleotide repeat expansion diseases, and motor neuron diseases, and to monitor their effect on neural circuits andbehaviour, which in turn allows genetic dissection of the underlying pathogenic mechanism(s).
Mentions: To date, there is no effective therapy or cure for MND. As is the case for AD and PD, the majority of MND cases are sporadic and the causes are unknown. However, the identification of protein aggregates (fragmented, phosphorylated, ubiquitinated) in intracellular inclusions as well as the analyses of heritable, familial cases led to the identification of genes involved in MND pathogenesis (Table 4). In some cases motor neuron death is caused by mutations in a single gene, such as survival of motor neurons (SMN) causing SMA [255]. For the majority of these disease-related genes, Drosophila homologues are present (Table 4) and movement disorders can be easily monitored in the fly (Fig. 4). Thus, loss- and gain-of-function analyses or mis-expression of the human disease gene have been used to establish fly models of MND.

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