Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy

Abstract

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 bortezomibcausing CIPN through its regulation of mitochondria dynamics.

Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer’s disease

“…eGFP cDNA was removed during the cloning process to produce an untagged TTL. For lentiviral shRNA expression, 2 TTL shRNA sequences, cloned in pLKO.1 vector, were purchased from Sigma- Aldrich: shTTL1 (TRCN0000191515, sequence: 5’ - CCG GCA TTC AGA AA GAG TAC TCA ACT CGA GTT GAC TAC TCT TTC TGA ATG CTT TTT TG - 3’) and shTTL2 (TRCN0000191227, sequence: 5’ - CCG GCT CAA AGA ACT ATG GGA AAT ACT CGA GTA TTT CCC ATA GTT CTT TGA GTT TTT TG - 3’) 35 . The SHC001 pLKO.1-puro Empty Vector (Sigma) was used as control (shControl).…”

“…Δ2 tubulin cannot be re- tyrosinated by TTL, and is thus removed from the Tyr/deTyr cycle 27, 32 . It follows that TTL suppression induces an accumulation of detyrosinated and Δ2 -tubulins, whereas TCP inhibition has the opposite effect 33–35 .…”

“…While the function of Δ2 tubulin remains unknown, it is very abundant in neurons where it accumulates on very long-lived MTs 32 . Unbuffered accumulation of Δ2 tubulin, however, has been recently associated with axonal degeneration that occurs following inhibition of mitochondrial motility 35 . In the brain, significant alteration of the Tyr/deTyr cycle from birth modifies the relative ratio of tyrosinated, detyrosinated and Δ2 tubulin, leading to severe neurodevelopmental phenotypes in mice 34, 61 .…”