Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150Glued Deacetylation by Axonal HDAC1

Amrita Pathak, Emily M. Stanley, F. Edward Hickman, Natalie Wallace, Bryson Brewer, Deyu Li, Shani Gluska, Eran Perlson, Sabine Fuhrmann, Katerina Akassoglou, Francisca Bronfman, Patrizia Casaccia, Dylan T. Burnette, Bruce D. Carter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

During development, neurons undergo apoptosis if they do not receive adequate trophic support from tissues they innervate or when detrimental factors activate the p75 neurotrophin receptor (p75NTR) at their axon ends. Trophic factor deprivation (TFD) or activation of p75NTR in distal axons results in a retrograde degenerative signal. However, the nature of this signal and the regulation of its transport are poorly understood. Here, we identify p75NTR intracellular domain (ICD) and histone deacetylase 1 (HDAC1) as part of a retrograde pro-apoptotic signal generated in response to TFD or ligand binding to p75NTR in sympathetic neurons. We report an unconventional function of HDAC1 in retrograde transport of a degenerative signal and its constitutive presence in sympathetic axons. HDAC1 deacetylates dynactin subunit p150Glued, which enhances its interaction with dynein. These findings define p75NTR ICD as a retrograde degenerative signal and reveal p150Glued deacetylation as a unique mechanism regulating axonal transport. Retrograde degenerative signaling is suggested to regulate neuronal survival and degeneration. Pathak et al. identify a retrograde degenerative signal involving the intracellular domain of p75 neurotrophin receptor and histone deacetylase, HDAC1, in sympathetic neurons. HDAC1 regulates retrograde axonal transport by deacetylating dynactin subunit p150Glued, enhancing its binding to dynein.

Original languageEnglish
Pages (from-to)376-387.e7
JournalDevelopmental Cell
Volume46
Issue number3
DOIs
StatePublished - 6 Aug 2018

Keywords

  • BDNF
  • HDAC1
  • NGF
  • P75NTR
  • axonal transport
  • dynactin
  • dynein
  • neurotrophin
  • p150
  • sympathetic

Fingerprint

Dive into the research topics of 'Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150Glued Deacetylation by Axonal HDAC1'. Together they form a unique fingerprint.

Cite this