TY - JOUR
T1 - Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy
AU - Pero, Maria Elena
AU - Meregalli, Cristina
AU - Qu, Xiaoyi
AU - Shin, Grace Ji Eun
AU - Kumar, Atul
AU - Shorey, Matthew
AU - Rolls, Melissa M.
AU - Tanji, Kurenai
AU - Brannagan, Thomas H.
AU - Alberti, Paola
AU - Fumagalli, Giulia
AU - Monza, Laura
AU - Grueber, Wesley B.
AU - Cavaletti, Guido
AU - Bartolini, Francesca
N1 - Funding Information:
This project was funded by a Thompson Family Foundation (TFFI) award to F.B. and G.C., a TFFI award to W.B.G., RO1AG050658 (NIH/National Institute on Aging) and R21NS120076 (NIH/ NINDS) awards to F.B., and a PRIN-2017FJC3-004 (MIUR) to G.C. and M.E.P. We are grateful to Gregg G. Gundersen for stimulating discussions and access to his microscopes. We thank Giuseppe Tosto for advising on statistical analysis of the data and Samie Jules for technical assistance in the analysis of the experiments with adult DRG neurons. Our gratitude goes to Annalisa Canta, Alessia Chiorazzi, Elisa Ballarini, and Virginia Rodriguez for technical assistance in rat behavior and neurophysiology experiments and to Luke Hammond for optimizing conditions for EB1 imaging in Drosophila. We are grateful to Terry Hafer for providing the sample preparation protocol for live imaging of Drosophila larvae, Robert Cudmore (Johns Hopkins) for Python codes for blinding files collected in Drosophila experiments, and the Zuckerman Institute’s Cellular Imaging platform for instrument use and technical advice for Drosophila imaging. We thank Elena Bianchetti and Markus D. Siegelin for assisting us with caspase cleavage assays.
Funding Information:
ACKNOWLEDGMENTS. This project was funded by a Thompson Family Foundation (TFFI) award to F.B. and G.C., a TFFI award to W.B.G., RO1AG050658 (NIH/National Institute on Aging) and R21NS120076 (NIH/ NINDS) awards to F.B., and a PRIN-2017FJC3-004 (MIUR) to G.C. and M.E.P. We are grateful to Gregg G. Gundersen for stimulating discussions and access to his microscopes. We thank Giuseppe Tosto for advising on statistical analysis of the data and Samie Jules for technical assistance in the analysis of the experiments with adult DRG neurons. Our gratitude goes to Annalisa Canta, Alessia Chiorazzi, Elisa Ballarini, and Virginia Rodriguez for technical assistance in rat behavior and neurophysiology experiments and to Luke Hammond for optimizing conditions for EB1 imaging in Drosophila. We are grateful to Terry Hafer for providing the sample preparation protocol for live imaging of Drosophila larvae, Robert Cudmore (Johns Hopkins) for Python codes for blinding files collected in Drosophila experiments, and the Zuckerman Institute’s Cellular Imaging platform for instrument use and technical advice for Drosophila imaging. We thank Elena Bianchetti and Markus D. Siegelin for assisting us with caspase cleavage assays.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/1/26
Y1 - 2021/1/26
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.2012685118
DO - 10.1073/pnas.2012685118
M3 - Article
C2 - 33468672
AN - SCOPUS:85100017888
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
M1 - e2012685118
ER -