Abstract
Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease. The primary symptoms of Parkinson's disease (PD) result from reduced activity of dopamine-secreting neurons caused by cell death in the pars compacta region of the substantia nigra. Microtubule associated protein Tau (MAPT) is a microtubule-associated protein linked with neurodegenerative diseases. Tau is a major component of the neurofibrillary tangles (NFT) found in PD. To test whether its microtubule binding repeat of Tau may be essential for its pathogenesis, we mutated the four microtubule binding motifs of human Tau and expressed these mutant protein in the dopaminergic neurons of Drosophila using GAL4-UAS system and using VMAT-pHluorin as a reporter. We found that Tau mutation on these four microtubule binding repeat reduced its toxicity compared to the neuronal degeneration of DA neurons induced by wild-type Tau. In addition, this mutant also showed normal VMAT-pHluorin expression pattern when flies aged to 4-week-old. Interestingly, we found FTDP-17 associated mutants effects on DA neuron with different severity, TauG272V>Tau WT>TauR406W. Moreover, Tau G272V blocking VMAT-pHluorin signaling, whereas Tau 406W did not. Taken together we suggested that the microtubule binding repeat of Tau play a critical role for Tau-mediated PD. Inhibition of the interplay of Tau and mitochondria may serve as a therapeutic target.