1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C.
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 (PKCdelta) 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.
Morfini
G
G
Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA. gmorfini@uic.edu
Pigino
G
G
Opalach
K
K
Serulle
Y
Y
Moreira
J E
JE
Sugimori
M
M
Llinás
R R
RR
Brady
S T
ST
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D049832:Decapodiformes; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects
D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium