Iron And Alpha-synuclein Correlate With The Selective Degeneration Of Nigra Dopaminergic Neurons In MPTP-induced PD Mouse Models

Parkinson's disease (PD) is an adult-onset progressive neurodegenerative disorder, which is characterized by bradykinesia, resting tremor, rigidity and gait disturbance. Neuropathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra (SN) and the formation of lewy bodies (LBs). There are three dopaminergic systems and different cell groups display different susceptibilities to cell death. Degeneration of the dopamine (DA) neurons in the substantia nigra (SN) is the most prominent, whereas, in the ventral tegmental area (VTA), DA neurons are less affected. This Phenomenon is also proved in animal models following the administration of toxic substances. MPTP is a classic toxic agent to induce PD mice models, the metabolites of MPTP is MPP+. Evidents showed that it was not because of the uptake of MPP+ that accounted for the differential toxicity observed with MPTP-treatedment, but because of the differential defense mechanism between the SN and the VTA, the mechanism is far from known. In order to investigate the mechanisms of the selective DA degeneration of neurons in the SN, we adopted chronic MPTP treated PD mouse models to observe the expression of TH, DMT1+IRE, DMT1-IRE, FP1, alpha-synuclein and the aggregations of alpha-synuclein in the SN and the VTA using immunohistochemistry, Perls'iron staining and electron microscopy. The results indicated that iron and alpha-synuclein correlate with the selective nigral degeneration of dopaminergic neurons.The results are as follows:1. The number of TH immunopositive cells in the SN was decreased by 70% in MPTP-treated mice compared with that of the control (P<0.05), while there was no significant change of TH positive cells in the VTA between the two groups.2. Using Perls' iron staining, we observed that the number of iron-positive cells was increased by 163% in the SN of MPTP-induced PD mice compared with that of the control (P<0.05), while there was no significant change in the VTA between the two groups.3. DMT1+IRE and DMT1-IRE positive cells were increased by 49% (P＜0.05) and 41% (P<0.05) in the SN in MPTP-induced PD mice compared with that of the control, respectively. However, there were no changes observed in the VTA.4. FP1 positive cells were decreased by 40% (P<0.05) in the SN in MPTP-treated mice compared with the control, while in the VTA these changes of FP1 positive cells were not observed.5. Granular aggregations of alpha-synuclein were observed in cytoplasm close to nucleus and even occured in dendrites in the SN of MPTP-induced mice detected by electron microscopy, but not in the VTA after MPTP treatment.6. The expression of alpha-synuclein was increased by 76% (P＜0.05) in the SN of MPTP treated mice compared with the control. No changes of the expression of alpha-synuclein were observed in the VTA of MPTP treated mice compared with the control.Results showed that the number of tyrosine hydroxylase (TH) immunoreactive neurons decreased and iron-staining positive cells increased in the SN, but not in the VTA. Increased expression of DMT1 and decreased expression of FP1 might associate with this increased nigral iron levels. Aggregations and up-regulation of a-synuclein were also observed only in the SN. These results suggest that increased iron levels, the misregulation of DMT1 and FP1, the aggregation and up-regulation of alpha-synuclein might associate with the different degeneration of DA neurons in SN and VTA.