神经生物学基底神经节疾病.ppt

Fig. 6. The neurotoxins used in animal models of PD induce mitochondrial dysfunction. MPTP is converted by monoamine oxidase B (MAO B) to MPP+. Like 6-OHDA, MPP+ is taken up by dopamine transporters and then can be accumulated by mitochondria, leading to complex I inhibition. In contrast to 6-OHDA, MPP+ can be taken up by vesicular monoamine transporters, which reduces the toxicity of MPP+. Paraquat and rotenone also inhibit mitochondrial complex I, whereas maneb inhibits the mitochondrial complex III. * Seed for LB * Fig. 1. Overview of the a-syn aggregation process integrated with the oxidative stress pathway and the UPP. The dynamics and interplay of these reaction modules affecting a-syn aggregation are graphically depicted. UPP model includes the steps of ubiquitination and clearance by the proteasome. Under normal conditions a-syn is cleared by the proteasome, while a-syn oligomers formed due to oxidative radical induced modifications of a-syn can be cleared by the lysosome. The proteasome is competitively inhibited by a-syn aggregates that form under oxidative stress thereby potentially reducing its clearance efficiency. Mutations in the proteasomal compartments such as mutation of the E3 ligase (PARK) or the mutation of the deubiquitinating enzyme UCH-L1 have been modeled by reducing the rate of clearance by the proteasome by a certain percentage (see simulation protocol). Oxidative stress pathway model includes all the reaction nodes that result in generating the ROS as summarized in the figure. A-syn aggregation module includes the modifications of a-syn by ROS, over-expression or mutations in a-syn, which form the a-syn seeds leading to formation of oligomers and a-syn aggregates. The aggregates inhibit UPP and also further increase ROS generation. * The PTEN-induced putative kinase 1 (PINK1) is a mitochondrially targeted serine–threonine kinase, which is linked to autosomal recessive familial parkinsonism. Current literature implicates PINK1 as a pivotal