The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.

Pero, M., Meregalli, C., Qu, X., Shin, G., Kumar, A., Shorey, M., et al. (2021). Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 118(4) [10.1073/pnas.2012685118].

Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy

Meregalli, Cristina
Secondo
;
Alberti, Paola;Fumagalli, Giulia;Monza, Laura;Cavaletti, Guido
Penultimo
;
2021

Abstract

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.
Articolo in rivista - Articolo scientifico
delta 2 tubulin, mitochondria, DRG, bortezomib, axonopathy;
English
26-gen-2021
2021
118
4
e2012685118
open
Pero, M., Meregalli, C., Qu, X., Shin, G., Kumar, A., Shorey, M., et al. (2021). Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 118(4) [10.1073/pnas.2012685118].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/299750
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