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+)...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 7; pp. 2442 - 2447 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
13.02.2007
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | 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 (PKCδ) 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed by R. R. Llinás, December 22, 2006 Author contributions: G.M., G.P., Y.S., J.E.M., M.S., R.R.L., and S.T.B. designed research; G.M., G.P., K.O., J.E.M., and S.T.B. performed research; G.M., G.P., J.E.M., and S.T.B. analyzed data; and G.M., G.P., R.R.L., and S.T.B. wrote the paper. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0611231104 |