Parkinson's disease (PD), a late-onset condition characterized by dysfunction and loss of dopaminergic neurons in the substantia nigra, has both sporadic and neurotoxic forms. Neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its metabolite 1-methyl-4-phenylpyridinium (MPP؉) induce PD symptoms and recapitulate major pathological hallmarks of PD in human and animal models. Both sporadic and MPP؉-induced forms of PD proceed through a ''dying-back'' pattern of neuronal degeneration in affected neurons, characterized by early loss of synaptic terminals and axonopathy. However, axonal and synaptic-specific effects of MPP؉ are poorly understood. Using isolated squid axoplasm, we show that MPP؉ produces significant alterations in fast axonal transport (FAT) through activation of a caspase and a previously undescribed protein kinase C (PKC␦) isoform. Specifically, MPP؉ increased cytoplasmic dynein-dependent retrograde FAT and reduced kinesin-1-mediated anterograde FAT. Significantly, MPP؉ effects were independent of both nuclear activities and ATP production. Consistent with its effects on FAT, MPP؉ injection in presynaptic domains led to a dramatic reduction in the number of membranous profiles. Changes in availability of synaptic and neurotrophin-signaling components represent axonal and synaptic-specific effects of MPP؉ that would produce a dying-back pathology. Our results identify a critical neuronal process affected by MPP؉ and suggest that alterations in vesicle trafficking represent a primary event in PD pathogenesis. We propose that PD and other neurodegenerative diseases exhibiting dying-back neuropathology represent a previously undescribed category of neurological diseases characterized by dysfunction of vesicle transport and associated with the loss of synaptic function.is the second most common neurodegenerative disease after Alzheimer's disease with 1% of people Ͼ50 and 5% of those Ͼ85 developing PD (1). First described in 1817, PD is associated with a dying back of axons projecting from substantia nigra pars compacta (SNpC) to the striatum. When Ͼ80% of striatal dopaminergic synapses from nigral neurons no longer function, a shortage of dopamine in the striatum causes the movement defects that characterize PD (2). Although the proximate cause of PD is well understood, molecular pathogenesis in PD remained unknown. Approximately 95% of PD cases are sporadic, with an undetermined fraction resulting from environmental factors like 1-methyl-4-phenylpyridinium (MPTP) and other toxins (3). Ideally, treatments that prevent loss of affected neurons and maintain neuronal function will be developed, but this requires a better understanding of underlying molecular pathogenesis in PD (2).PD is unique among adult-onset neurodegenerative diseases in the existence of toxin-mediated forms of the disease that mirror the neuropathology observed in sporadic PD. MPTP and its metabolite 1-methyl-4-phenylpyridinium (MPPϩ) is the best-characterized example of a toxin-induced PD (4), although others such as p...