1-methyl-4-phenylpyridinium Affects Fast Axonal Transport by Activation of Caspase and Protein Kinase C.
From: Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA. gmorfini@uic.edu
Proceedings of the National Academy of Sciences of the United States of America
- Publish Date: Feb 2007
- ISSN: 0027-8424
- Volume: 104
- Issue: 7
- Pages: 2442-7
- Medium: Print
- Language: English
- Citation (JAMA): Morfini G, Pigino G, Opalach K, et al. 1-methyl-4-phenylpyridinium Affects Fast Axonal Transport by Activation of Caspase and Protein Kinase C.. Proc. Natl. Acad. Sci. U.S.A. Feb 2007;104:2442-7
Abstract
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.
Mesh Headings (Keywords): 1-Methyl-4-phenylpyridinium, Animals, Axonal Transport, Caspases, Decapodiformes, Disease Models, Animal, Enzyme Activation, Kinetics, Neurons, Parkinson Disease, Protein Kinase C, Protein Kinase C-delta, Synaptic Vesicles
Check for Full Text / PubMed Unique Identifier (PMID): 17287338
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