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

Keiichi Tamai, Masafumi Toyoshima, Nobuyuki Tanaka, Noriko Yamamoto, Yuji Owada, Hiroshi Kiyonari, Kazuko Murata, Yoshiyuki Ueno, Masao Ono, Tooru Shimosegawa, Nobuo Yaegashi, Masahiko Watanabe, Kazuo Sugamura

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

Abstract

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 hrsflox/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 hrsflox/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.

Original languageEnglish
Pages (from-to)1806-1817
Number of pages12
JournalAmerican Journal of Pathology
Volume173
Issue number6
DOIs
Publication statusPublished - 2008 Dec

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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