2017 Volume 34 Issue 2 Pages 67-70
Current treatments for Parkinson's disease (PD) are mainly based on medications such as levodopa, dopamine agonists, and inhibitors of dopamine metabolisms. However, it is impossible to halt the progression of the disease. Thus, it is necessary to develop a disease modifying therapy for PD. Therefore, we need the animal models including Drosophila. At present, simple model organisms such as Drosophila are being very useful for the study of genes and pathways involved in a wide range of disorders, mainly due to the similarity of its biological pathways to those of humans. Interestingly, the fly has been successfully used for elucidating the pathogenesis of the diseases. Perry syndrome, involving mutations in the dynein motor component dynactin or p150Glued, is characterized by TDP–43 pathology in affected brain regions, including the substantia nigra. However, the molecular relationship between p150Glued and TDP–43 is largely unknown. Here, we report that a reduction in TDP–43 protein levels alleviates the synaptic defects of neurons expressing the Perry mutant p150G50R in Drosophila. Dopaminergic expression of p150G50R, which decreases dopamine release, disrupts motor ability and reduces the lifespan of Drosophila. p150G50R expression also causes aggregation of dense core vesicles (DCVs), which contain monoamines and neuropeptides, and disrupts the axonal flow of DCVs, thus decreasing synaptic strength. The above phenotypes associated with Perry syndrome are improved by the removal of a copy of Drosophila TDP–43 TBPH, thus suggesting that the stagnation of axonal transport by dynactin mutations promotes TDP–43 aggregation and interferes with the dynamics of DCVs and synaptic activities. In this study, regulation of TDP–43 expression could be one strategy for development of new therapies. In addition, Drosophila model could be a useful tool for elucidating of the pathomechanisms of the several genetic diseases.