NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization

Nat Commun. 2014 Feb 25;5:3354. doi: 10.1038/ncomms4354.

Abstract

Nuclear transcription factor-Y (NF-Y), a key regulator of cell-cycle progression, often loses its activity during differentiation into nonproliferative cells. In contrast, NF-Y is still active in mature, differentiated neurons, although its neuronal significance remains obscure. Here we show that conditional deletion of the subunit NF-YA in postmitotic mouse neurons induces progressive neurodegeneration with distinctive ubiquitin/p62 pathology; these proteins are not incorporated into filamentous inclusion but co-accumulated with insoluble membrane proteins broadly on endoplasmic reticulum (ER). The degeneration also accompanies drastic ER disorganization, that is, an aberrant increase in ribosome-free ER in the perinuclear region, without inducing ER stress response. We further perform chromatin immunoprecipitation and identify several NF-Y physiological targets including Grp94 potentially involved in ER disorganization. We propose that NF-Y is involved in a unique regulation mechanism of ER organization in mature neurons and its disruption causes previously undescribed novel neuropathology accompanying abnormal ubiquitin/p62 accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • CCAAT-Binding Factor / genetics
  • CCAAT-Binding Factor / metabolism*
  • Cell Line, Tumor
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / physiology
  • Female
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Sequestosome-1 Protein
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • CCAAT-Binding Factor
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Membrane Proteins
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Ubiquitin
  • glucose-regulated proteins
  • nuclear factor Y