Paclitaxel Reduces Axonal Bclw to Initiate IP 3 R1-Dependent Axon Degeneration

Neuron. 2017 Oct 11;96(2):373-386.e6. doi: 10.1016/j.neuron.2017.09.034.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many cancer treatments. The hallmark of CIPN is degeneration of long axons required for transmission of sensory information; axonal degeneration causes impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that the chemotherapeutic agent paclitaxel triggers CIPN by altering IP3 receptor phosphorylation and intracellular calcium flux, and activating calcium-dependent calpain proteases. Concomitantly paclitaxel impairs axonal trafficking of RNA-granules and reduces synthesis of Bclw (bcl2l2), a Bcl2 family member that binds IP3R1 and restrains axon degeneration. Surprisingly, Bclw or a stapled peptide corresponding to the Bclw BH4 domain interact with axonal IP3R1 and prevent paclitaxel-induced degeneration, while Bcl2 and BclxL cannot do so. Together these data identify a Bclw-IP3R1-dependent cascade that causes axon degeneration and suggest that Bclw-mimetics could provide effective therapy to prevent CIPN.

Keywords: Axon degeneration; Bclw (Bcl2l2); IP(3)R1; RNA transport; SFPQ; calpain; chemotherapy-induced peripheral neuropathy; paclitaxel.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents, Phytogenic / toxicity
  • Axons / drug effects
  • Axons / metabolism*
  • Axons / pathology
  • Cells, Cultured
  • Female
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Degeneration / chemically induced*
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Paclitaxel / toxicity*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Antineoplastic Agents, Phytogenic
  • Bcl2l2 protein, rat
  • Inositol 1,4,5-Trisphosphate Receptors
  • Itpr1 protein, rat
  • Proto-Oncogene Proteins c-bcl-2
  • Paclitaxel