Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP⁺-induced neurodegeneration

J. Neurochem. (2010) 115, 247-258. Dysfunction of the microtubule (MT) system is an emerging theme in the pathogenesis of Parkinson's disease. This study was designed to investigate the putative role of MT dysfunction in dopaminergic neuron death induced by the neurotoxin 1-methyl-4-phenylpirid...

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Published in:	Journal of neurochemistry Vol. 115; no. 1; pp. 247 - 258
Main Authors:	Cartelli, Daniele, Ronchi, Cristina, Maggioni, Maria G, Rodighiero, Simona, Giavini, Erminio, Cappelletti, Graziella
Format:	Journal Article
Language:	English
Published:	Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.10.2010 Blackwell Publishing Ltd Wiley-Blackwell
Subjects:	1-methyl-4-phenylpiridinium Adenosine Triphosphate - metabolism Animals Axonal transport Axonal Transport - drug effects Axonogenesis Biological and medical sciences Biological Transport, Active Blotting, Western Caspase 3 - metabolism Caspase Inhibitors Caspase-3 Cell Death - drug effects Cellular biology Data processing Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Dopamine Enzyme Inhibitors - pharmacology Fluorescent Antibody Technique Injuries live cell imaging Medical sciences Membrane Potentials - drug effects microtubule Microtubules Microtubules - drug effects Microtubules - metabolism Microtubules - pathology Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology Mitochondrial Membranes - drug effects Movement disorders MPP super(+) MPTP Poisoning - metabolism MPTP Poisoning - pathology Nerve Degeneration - metabolism Nerve Degeneration - pathology Nerves Nervous system (semeiology, syndromes) Nervous system as a whole Neurites - drug effects Neurites - metabolism Neurochemistry Neurodegeneration Neurodegenerative diseases Neurology neuronal death Neurons Neurotoxins Parkinson disease Parkinson's disease PC12 Cells Pheochromocytoma cells Photobleaching Post-translation Protein Kinase C - antagonists & inhibitors Protein Kinase C - metabolism Protein Kinase Inhibitors - pharmacology Rats Tubulin Modification Skin disease Parkinson's disease Pathogenesis Biological transport Alteration Parkinson disease Cardiovascular disease Nerve growth factor Venous disease Vascular disease Mitochondria Dynamics axonal transport Varicosity Degenerative disease Nervous system diseases live cell imaging Cerebral disorder Toxin Cell death Dysfunction 1-methyl-4-phenylpiridinium neuronal death Central nervous system disease Neurotoxin Cytoskeleton Dopaminergic neuron Microtubule Extrapyramidal syndrome
ISSN:	0022-3042, 1471-4159, 1471-4159
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Summary:	J. Neurochem. (2010) 115, 247-258. Dysfunction of the microtubule (MT) system is an emerging theme in the pathogenesis of Parkinson's disease. This study was designed to investigate the putative role of MT dysfunction in dopaminergic neuron death induced by the neurotoxin 1-methyl-4-phenylpiridinium (MPP⁺). In nerve growth factor-differentiated PC12 cells, we have analyzed post-translational modifications of tubulin known to be associated with differently dynamic MTs and show that MPP⁺ causes a selective loss of dynamic MTs and a concomitant enrichment of stable MTs. Through a direct live cell imaging approach, we show a significant reduction of MT dynamics following exposure to MPP⁺ and a reorientation of MTs. Furthermore, these alterations precede the impairment of intracellular transport as revealed by changes in mitochondria movements along neurites and their accumulation into varicosities. We have also analyzed activation of caspase 3 and mitochondrial injury, well-known alterations induced by MPP⁺, and found that they are noticeable only when MT dysfunction is already established. These data provide the first evidence that axonal transport impairment and mitochondrial damage might be a consequence of MT dysfunction in MPP⁺-induced neurodegeneration, lending support to the concept that alterations of MT organization and dynamics could play a pivotal role in neuronal death in Parkinson's disease.
Bibliography:	http://dx.doi.org/10.1111/j.1471-4159.2010.06924.x SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2
ISSN:	0022-3042 1471-4159 1471-4159
DOI:	10.1111/j.1471-4159.2010.06924.x