Reduced TDP-43 Expression Improves Neuronal Activities in a Drosophila Model of Perry Syndrome

Parkinsonian 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. [Display omitted] •Fly model of Perry syndrome exhibits motor disturbance and impaired dopamine release.•Perry mutation in dynactin produces aggregation of dense core vesicles (DCVs) in axons and disrupts axonal flux of DCVs.•Removal of a copy of the TDP-43 gene improves retrograde flux of DCVs. Parkinsonian Perry syndrome (PS), caused by mutations in a component of the retrograde transport complex, Dynactin, is pathologically characterized by the accumulation of an RNA-binding protein, TDP-43, in affected neurons. The neuronal accumulation of TDP-43 is observed in various neurodegenerative diseases including amyotrophic lateral sclerosis and Alzheimer's disease. We report that decreased TDP-43 expression improves defects in the axonal transport of dense core vesicles and in the dopamine release in a Drosophila PS model. This study provides insight into the possibility that a transient decrease in TDP-43 in neurons may be a promising therapeutic approach for treating neurodegenerative disorders associated with TDP-43 pathology, including PS.