Neurodegenerative diseases are among some of the most devastating diseases afflicting humans. Examples of neurodegenerative diseases include Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and spinocerebellar ataxia (SCA). However, the discovery and development of therapeutics for disorders of the central nervous system (CNS), particularly for neurodegenerative diseases, has historically been very difficult.
The investigation of pathogenic mechanisms in neurodegenerative disease has been facilitated by the recent development of disease models in Drosophila. By introducing human disease genes with dominant gain-of-function mutations into Drosophila, models for a number of neurodegenerative diseases have been generated, including models for Huntington's disease and spinocerebellar ataxia (see, for example, Chan et al. (2000) Cell Death Differ. 7:1075-1080; Feany et al. (2000) Nature 404:394-398; Femandez-Funez et al. (2000) Nature 408:101-106; Fortini et al. (2000) Trends Genet. 16:161-167; Jackson et al. (1998) Neuron 21:633-642; Kazemi-Esfarjani et al. (2000) Science 287:1837-1840; Warrick et al. (1998) Cell 93:939-949. Specific cell or tissue expression can be achieved by placing the human gene under control of the GAL4/UAS transcriptional activation system from yeast (Brand et al. (1993) Development 118:401-415). Due to the ease with which genetic studies can be pursued in Drosophila, these models have been especially useful in identifying genes that modify the disease.
In some cases, expression of the transgene recapitulates one or more neuropathological features of the human disease. For example, in a Drosophila model for Parkinson's disease produced by neuronal expression of human mutated alpha-synuclein, age-dependent, progressive degeneration of dopamine-containing cells is seen accompanied by the presence of Lewy bodies that resemble those seen in the human disease, both by their immunoreactivity for alpha-synuclein and by their appearance in the electron microscope (Feany et al. (2000)). In the SCA182Q flies, expression of the mutated human ataxin-1 (associated with SCA) is accompanied by adult-onset degeneration of neurons, with nuclear inclusions that are immunologically positive for the mutated protein, ubiquitin, Hsp70 and proteosome components (Fernandez-Funez et al. (2000)). In the case of Huntington's disease, expression of exon-1 of huntingtin, containing an expanded polyglutamine repeat, causes a progressive degeneration, whose time of onset and severity are linked to the length of the repeat, as is seen in the human disease (Marsh et al. (2000) Hum. Mol. Genet. 9:13-25).
Although great advances have been made in understanding the biological basis of neurological disorders, this scientific progress has generally not yet been translated into effective new treatments for these devastating disorders. There remains a tremendous need for new methods of drug discovery for CNS disorders, particularly for neurodegenerative diseases.