Paclitaxel induces axonal microtubules polar reconfiguration and impaired organelle transport: implications for the pathogenesis of paclitaxel-induced polyneuropathy.
In differentiated axons almost all microtubules (MTs) uniformly point their plus ends towards the axonal tip. The uniform polar pattern provides the structural substrate for efficient organelle transport along axons. It is generally believed that the mass and pattern of MTs polar orientation remain unchanged in differentiated neurons. Here we examined long-term effects of the MTs stabilizing reagent paclitaxel (taxol) over MTs polar orientation and organelle transport in cultured Aplysia neurons. Unexpectedly, we found that rather than stabilizing the MTs, paclitaxel leads to their massive polar reconfiguration, accompanied by impaired organelle transport. Washout of paclitaxel does not lead to recovery of the polar orientation indicating that the new pattern is self-maintained. Taken together the data suggest that MTs in differentiated neurons maintain the potential to be reconfigured. Such reconfiguration may serve physiological functions or lead to degeneration. In addition, our observations offer a novel mechanism that could account for the development of peripheral neuropathy in patients receiving paclitaxel as an antitumor drug.
Shemesh
Or A
OA
Department of Neurobiology, Institute of Life Science, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Spira
Micha E
ME
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001048:Aplysia; D001369:Axons / Q000187:drug effects* / Q000473:pathology*; D001692:Biological Transport / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D018613:Microscopy, Confocal; D008870:Microtubules / Q000187:drug effects* / Q000473:pathology; D015388:Organelles / Q000187:drug effects; D017239:Paclitaxel / Q000633:toxicity*; D011115:Polyneuropathies / Q000139:chemically induced* / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel