Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+ -induced neurodegeneration.
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.
Cartelli
Daniele
D
Dipartimento di Biologia, Università degli Studi di Milano, Milan, Italy.
Ronchi
Cristina
C
Maggioni
Maria G
MG
Rodighiero
Simona
S
Giavini
Erminio
E
Cappelletti
Graziella
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D001693:Biological Transport, Active; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000187:drug effects; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D038761:Photobleaching; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D053148:Caspase 3