Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model.
We tested the hypothesis that microtubule (MT)-binding drugs could be therapeutically beneficial in tauopathies by functionally substituting for the MT-binding protein tau, which is sequestered into inclusions of human tauopathies and transgenic mouse models thereof. Transgenic mice were treated for 12 weeks with weekly i.p. injections of 10 or 25 mg/m(2) paclitaxel (Paxceed). Both doses restored fast axonal transport in spinal axons, wherein MT numbers and stable (detyrosinated) tubulins were increased, compared with sham treatment, and only Paxceed ameliorated motor impairments in tau transgenic mice. Thus, MT-stabilizing drugs could have therapeutic potential for treating neurodegenerative tauopathies by offsetting losses of tau function that result from the sequestration of this MT-stabilizing protein into filamentous inclusions.
Zhang
Bin
B
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce Street, Philadelphia, PA 19104, USA.
Maiti
Arpita
A
Shively
Sharon
S
Lakhani
Fara
F
McDonald-Jones
Gaye
G
Bruce
Jennifer
J
Lee
Edward B
EB
Xie
Sharon X
SX
Joyce
Sonali
S
Li
Chi
C
Toleikis
Philip M
PM
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D016875:tau Proteins; D017239:Paclitaxel