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Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program
Stefanie Geisler, … , Jeffrey Milbrandt, Aaron DiAntonio
Stefanie Geisler, … , Jeffrey Milbrandt, Aaron DiAntonio
Published September 5, 2019
Citation Information: JCI Insight. 2019;4(17):e129920. https://doi.org/10.1172/jci.insight.129920.
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Research Article Cell biology Neuroscience

Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program

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Abstract

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge on a core axon degeneration program consisting of nicotinamide mononucleotide NMNAT2, SARM1, and loss of NAD+ but engage different upstream mechanisms that closely resemble Wallerian degeneration after vincristine and apoptosis after bortezomib. We could inhibit the final common axon destruction pathway by preserving axonal NAD+ levels or expressing a candidate gene therapeutic that inhibits SARM1 in vitro. We suggest that these approaches may lead to therapies for vincristine- and bortezomib-induced neuropathies and possibly other forms of peripheral neuropathy.

Authors

Stefanie Geisler, Ryan A. Doan, Galen C. Cheng, Aysel Cetinkaya-Fisgin, Shay X. Huang, Ahmet Höke, Jeffrey Milbrandt, Aaron DiAntonio

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Figure 5

Vincristine- but not BTZ-induced axon degeneration is modulated by a MAPK pathway.

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Vincristine- but not BTZ-induced axon degeneration is modulated by a MAP...
(A and B) DRG neurons were treated with 1 μM of the DLK inhibitor GNE-3511 12 hours before adding vincristine (A) or BTZ (B), and axon degeneration was determined at indicated time points. (A) GNE-3511 decreases vincristine-induced axon degeneration. Two-way ANOVA showed significant effects for group F (3, 12) = 352.5, P < 0.0001; time F (4, 48) = 515.8, P < 0.0001; and interaction F (12, 48) = 205.6, P < 0.0001. Tukey’s multiple-comparisons test, ****P < 0.0001 (n = 4). In contrast, GNE-3511 does not decrease axon degeneration after BTZ administration (B). There was instead a small increase in axon fragmentation (n = 4). (C and D) DRG neurons obtained from Cas9-knockin mice expressing guide RNAs to MKK4 and -7 (gMKK4&7) or scrambled guide RNAs (gScram) were treated with vincristine (C) or BTZ (D), and axon degeneration was determined over time. Inhibiting MKK4 and -7 decreased vincristine-induced axon degeneration (C) but did not affect BTZ-induced axon degeneration (D). A 2-way ANOVA in C showed significant effects of group F (2, 12) = 30.64, P < 0.0001; time F (4, 48) = 100.2, P < 0.0001; and interaction F (8, 48) = 29.5, P < 0.0001. Tukey’s multiple-comparisons test, ***P < 0.001; ****P < 0.0001 (n = 5) (C and D). (E) Axon-only extracts derived from DRG neurons treated with the DLK inhibitor GNE-3511 and for 12 hours with vehicle, vincristine, or BTZ were immunoblotted for endogenous NMNAT2. GNE-3511 increased endogenous NMNAT2 12 hours after vehicle and vincristine but not following BTZ administration. Paired t tests, *P < 0.05; n = 4.

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