Loss of hrs in the central nervous system causes accumulation of ubiquitinated proteins and neurodegeneration

Am J Pathol. 2008 Dec;173(6):1806-17. doi: 10.2353/ajpath.2008.080684. Epub 2008 Nov 13.


The endosomal sorting complex required for transport (ESCRT) proteins form multimolecular complexes that control multivesicular body formation, endosomal sorting, and transport ubiquitinated membrane proteins (including cell-surface receptors) to the endosomes for degradation. There is accumulating evidence that endosomal dysfunction is linked to neural cell degeneration in vitro, but little is known about the relationship between neural disorders and ESCRT proteins in vivo. Here we specifically deleted the hrs gene, ESCRT-0, in the neurons of mice by crossing loxP-flanked hrs mice with transgenic mice expressing the synapsin-I Cre protein (SynI-cre). Histological analyses revealed that both apoptosis and a loss of hippocampal CA3 pyramidal neurons occurred in the hrs(flox/flox);SynI-cre mice. Notably, the hrs(flox/flox);SynI-cre mice accumulated ubiquitinated proteins, such as glutamate receptors and an autophagy-regulating protein, p62. These molecules are particularly prominent in the hippocampal CA3 neurons and cerebral cortex with advancing age. Accordingly, we found that both locomotor activity and learning ability were severely reduced in the hrs(flox/flox);SynI-cre mice. These data suggest that Hrs plays an important role in neural cell survival in vivo and provide an animal model for neurodegenerative diseases that are known to be commonly affected by the generation of proteinaceous aggregates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Central Nervous System* / metabolism
  • Central Nervous System* / pathology
  • Disks Large Homolog 4 Protein
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes / metabolism
  • Guanylate Kinases
  • Hippocampus / cytology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Learning / physiology
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / physiology
  • Multiprotein Complexes / metabolism*
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Phenotype
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Receptors, Glutamate / metabolism
  • Synapsins / genetics
  • Synapsins / metabolism
  • Transcription Factor TFIIH
  • Transcription Factors / metabolism
  • Ubiquitination*
  • Weight Loss


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Endosomal Sorting Complexes Required for Transport
  • Gtf2h1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • Phosphoproteins
  • Receptors, Glutamate
  • Synapsins
  • Transcription Factors
  • hepatocyte growth factor-regulated tyrosine kinase substrate
  • Transcription Factor TFIIH
  • Guanylate Kinases