Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy

The pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bo...

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Published inbioRxiv
Main Authors Pero, Maria Elena, Meregalli, Cristina, Qu, Xiaoyi, Kumar, Atul, Shorey, Matthew, Rolls, Melissa, Tanji, Kurenai, Brannagan, Thomas, Alberti, Paola, Fumagalli, Giulia, Monza, Laura, Cavaletti, Guido, Bartolini, Francesca
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 02.08.2019
Subjects
Bortezomib
Chemotherapy
Cytoskeleton
Mitochondria
Motility
Neurodegeneration
Peripheral neuropathy
Sensory neurons
Tubulin
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Summary:The pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bort-induced peripheral neuropathy in humans. Furthermore, while induction of D2 was sufficient to cause axonopathy and inhibit mitochondria motility, reducing D2 alleviated both axonal degeneration and loss of mitochondria motility promoted by Bort. Altogether, our data demonstrate that Bort, structurally unrelated to tubulin poisons, can affect the tubulin cytoskeleton in sensory neurons in vitro, in vivo and in humans, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. They further reveal a previously unrecognized pathogenic role for D2 in bortezomib-causing CIPN through its regulation of mitochondria dynamics.
DOI:10.1101/721852