MPTP neurotoxicity: Actions, mechanisms, and animal modeling of parkinson's disease

Abstract

The study of neurotoxicity induced by MPTP led to drastically change the perspective on Parkinson's Disease. In fact the selective neurotoxicity induced by MPTP rejuvenated PD research and generated a number of studies aimed at elucidating the mechanisms of action of MPTP. Remarkably, these molecular mechanisms turned out to be critical also for the survival of DA neurons in idiopathic PD. In this chapter we report the main concepts developed over the last three decades to understand key molecular steps which are pivotal in MPTP toxicity. This is the case of the role played by DAT and VMAT-2 in conditioning the sensitivity to MPTP neurotoxicity. Similarly, the mitochondria as targets of MPTP toxicity appear similarly affected by selective mutation of genes leading to PD. Again, the fate of mitochondria and the ability to clear these organelles when being dysfunctional is key in the modulation of MPTP toxicity. This also applies for misfolded proteins such as alpha synuclein. Again, multiple brain areas as well as peripheral sites are increasingly recognized to be affected both during MPTP toxicity and sporadic PD patients. Nowadays it seems that MPTP per se did not lead to discovery of the environmental compound which causes PD, nonetheless the study of MPTP did disclose several molecular and cellular pathways which are critical in the genesis of PD. This latter point fairly corresponds to what we enthusiastically expected from MPTP when it was identified as a causal agent of what it remains, a toxic form of environmental parkinsonism.