Invertebrate Models

The Parkinson's-Reversing Breakthrough

Parkinson Disease Treatment

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Although the anatomical differences between Homo sapiens and Drosophila melanogaster are somewhat dramatic, invertebrates such as D. melanogaster are now providing an important avenue for understanding neurodegenerative disorders (208). Similar to studies in rodents, flies have served as a template for exposure to toxins implicated in PD, including rotenone and paraquat (209). A number of recently identified genes involved in familial forms of PD, including alpha-synuclein, parkin, and DJ-1, in conjunction with the molecular tools available for gene transfer, have resulted in the establishment of transgenic fly lines expressing these genes (210). These new models are significant because they can be used to elucidate the biochemical function of these proteins, identify other interacting proteins and regulatory genes, and because of their less expensive costs and potential for high volume screening ultimately can be used to screen large chemical libraries for new therapeutic agents (211). One of the first examples of fly models of human neurodegenerative disorders was the introduction of both wild-type and mutant forms of human alpha-synuclein that resulted in loss of tyrosine hydroxylase dopaminergic neurons, the formation of intra-cytoplasmic and neurite protein aggregates, and progressive motor behavior impairment (210). The availability of powerful transposon-based screens can be used to find compensatory mutants and proteins that interact with alpha-synuclein, such as the chaperone protein Hsp-70, thus providing insights into structure and function relationships (212).

The success of alpha-synuclein transgenic flies has provided a strong foundation for the development of other transgenic D. melanogaster models. For example, targeting the parkin gene, despite showing little evidence of specific dopaminergic neuron cell death (213), do manifest mitochondrial pathology and neuromuscular dysfunction (214). In addition, they show increased sensitivity to oxidative stress and wide-scale degeneration, which may provide insight into the relationship between vulnerability of high-energy demand cells to injury and death (215). Another example of the impact of D. melanogaster models in neurodegenerative disorders is the demonstration of the development of DJ-1 transgenic flies. D. melanogaster possess two alleles of DJ-1, but P-element-based gene disruption leads to impaired climbing ability that is progressive with age and localization to mitochondria, but no apparent loss of dopaminergic neurons (216). Recent studies in D. melanogaster suggest that DJ-1 may function as a redox-sensitive molecular chaper-one that can protect against oxidative stress, underlying the susceptibility of mitochondria (217). Hence, flies with disruption of DJ-1 show increased sensitivity to induction of oxidative stress by hydrogen peroxide, rotenone, and paraquat (218). These studies highlight insights into the function of DJ-1 in D. melanogaster and provide a better understanding of its potential role in PD (219).

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