Figure 5.

Model for alteration of FAT as a mechanism leading to MPTP/MPP+-induced parkinsonism. Certain toxic chemicals, like MPTP and its metabolite MPP+, can produce a severe parkinsonism, but the pathogenic process was poorly understood. Agents like MPP+, rotenone, and paraquat are thought to act at the level of mitochondria, but mitochondria are ubiquitous and the neurodegenerative parkinsonian phenotype is highly selective (Dauer and Przedborski, 2003). In isolated axons, MPP+ activates caspase 3, which cleaves and activates a specific isoform of protein kinase C, PKCδ. Activated PKCδ then phosphorylates dynein intermediate chains and activate retrograde FAT. Further, activation of PKCδ reduces anterograde FAT. These imbalances in FAT result in depletion of synaptic vesicles from synapses, failure of neurotransmission (Morfini et al., 2007c; Serulle et al., 2007), and altered trophic factor support (Delcroix et al., 2004). These events ultimately would lead to neuronal cell death. cat, Catalytic subunit; reg, regulatory subunit.