REDD2-mediated inhibition of mTOR promotes dendrite retraction induced by axonal injury

Cell Death Differ. 2015 Apr;22(4):612-25. doi: 10.1038/cdd.2014.149. Epub 2014 Sep 26.

Abstract

Dendritic defects occur in neurodegenerative diseases accompanied by axonopathy, yet the mechanisms that regulate these pathologic changes are poorly understood. Using Thy1-YFPH mice subjected to optic nerve axotomy, we demonstrate early retraction of retinal ganglion cell (RGC) dendrites and selective loss of mammalian target of rapamycin (mTOR) activity, which precede soma loss. Axonal injury triggered rapid upregulation of the stress-induced protein REDD2 (regulated in development and DNA damage response 2), a potent inhibitor of mTOR. Short interfering RNA-mediated REDD2 knockdown restored mTOR activity and rescued dendritic length, area and branch complexity in a rapamycin-dependent manner. Whole-cell recordings demonstrated that REDD2 depletion leading to mTOR activation in RGCs restored their light response properties. Lastly, we show that REDD2-dependent mTOR activity extended RGC survival following axonal damage. These results indicate that injury-induced stress leads to REDD2 upregulation, mTOR inhibition and dendrite pathology causing neuronal dysfunction and subsequent cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Axons / metabolism*
  • DNA-Binding Proteins
  • Dendrites / drug effects
  • Dendrites / physiology*
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mice, Transgenic
  • Optic Nerve Injuries / metabolism
  • Optic Nerve Injuries / pathology*
  • Patch-Clamp Techniques
  • Proteins / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*
  • Thy-1 Antigens / genetics
  • Transcription Factors
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Ddit4l protein, mouse
  • Immunosuppressive Agents
  • Proteins
  • RNA, Small Interfering
  • Thy-1 Antigens
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus