Targeted overexpression of α-synuclein by rAAV2/1 vectors induces progressive nigrostriatal degeneration and increases sensitivity to MPTP in mouse

Aim α-synuclein genes including its mutations, duplication and triplication are the first identified ge- netic factor involved in the progress of PD. And α-synuclein （α-syn） is the main component in pathological hall- mark of PD, termed as Lewy bodies （LB）. Methods Human wild-type α-syn was stereotactic injected through rAAV2/1 vectors in the bilateral $N of mouse and examined the effects for up to 12 weeks. Results Delivery of rAAV-2/1-α-syn caused significant SN degeneration accompanied with appearance of dystrophic striatal neurites, loss of nigral dopaminergic （DA） neurons and dissolving nigral neuron bodies in a time-dependent manner. In ad- dition, the α-syn overexpressed mice also developed significant deficits in locomotor function at 12 weeks when the loss of DA neurons exceeded a threshold of 50%. To investigate the sensitivity to MPTP in α-syn-overexpressed mice, mice that were treated with rAAV for 8 weeks were injected with MPTP for five subsequent days. The insults on DA neuronal loss, striatal dopamine depletion, dopamine turnover and locomotor dysfunction were significantly increased compared with mice without α-syn overexpression. Furthermore, increased phosphorylation （S129） was accumulation and after the combined insults. Conclusions The overexpressed α-syn induces progressive nigrostri- atal degeneration and increases the sensitivity of DA neurons to MPTP. And the targeted overexpression of α-syn and the combination with environmental toxins may provide valuable models for PD researches.