Die Rolle von α-Synuclein im MPTP- und 6-OHDA-Modell des Morbus Parkinson

Parkison’s Disease (PD) is one of the most common neurodegenerative diseases. It causes death of dopaminerg neurones in the substantia nigra. PD is associated with the presence of abnormal aggregates of protein in the brain of PD patients called Lewy bodies. Lewy bodies are small, eosinophilic, cytoplasmic inclusions of which alpha-synuclein (α-syn) is a main component. After discovery of a mutation in the gentic code of α-syn causing early-onset form of PD scientists became interested in the α-syn. However, until now the role of α-syn is not yet clear. It has been proposed that α-syn has an effect on the oxidative stress by increasing the level of reactive oxygen species and hence, it exhibits a negative impact on cells in the substantia nigra. In the presented study on the influence of α-syn on two animal models of PD the subchronic MPTP and the 6-OHDA model was examined. The study used α-syn wild-type and knock-out mice treated with the toxins. The investigation showed that - deletion of α-syn is a protection against MPTP - protection is also shown in the 6-OHDA model on cellular level - pharmacokinetics of MPTP is not different in wild-type compared to knock-out mice - protection in α-syn deleted mice is not due to decreasing rate of reactive oxygen species In conclusion, it is possible that the observed effect of α-syn as a radical enhancer depends on the PD model and the toxin. Since the MPTP model contains less hydroxyl radicals than the 6-OHDA model it could be that the effects of α-syn on free radicals directly depend upon the of oxidative stress. The effects of 6-OHDA and MPTP on α-syn gene expression are contrary because MPTP increases α-syn mRNA concentration in cells whereas 6-OHDA decreases the α-syn mRNA concentration. Eventually 6-OHDA and not MPTP leads to an aggregation of α-syn in-vitro. The aggregation of α-syn could lead to an increasing rate of reactive oxygen species in the microglia. To validate this hypothesis further studies are required with other PD-models in which the radical concentration is detected. The inhibition of UPS with MPTP or 6-OHDA may be less in absence of α-syn. UPS could play a role in both models because MPTP and 6-OHDA inhibit the UPS. In addition, other studies have shown the UPS to play an important role in the vulnerability of α-syn knock-out mice. Additional specific studies should be performed to detect the inhibition of UPS with MPTP and 6-OHDA in wild-type and knock-out mice. In this study the role of α-syn could not be fully revealed but it brought out some significant results indicating that α-syn is not a radical enhancer per se. Revealing the full role of α-syn in PD could be the key for understanding the pathogenesis and therefore, could open new strategies of therapy.