Frank Hirth Pages 504 - 523 ( 20 )
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 Alzheimers, Parkinsons, and motor neuron diseases, as well as models for trinucleotide repeat expansion diseases, including ataxias and Huntingtons 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.
Alzheimer's disease, Parkinson's disease, motor neuron disease, trinucleotide repeat expansion disease, c-Jun N-terminal kinase, bone morphogenetic protein, neurodegeneration, Drosophila
King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, Department of Neuroscience, PO Box 37, 16 De Crespigny Park, London SE5 8AF, UK.