Published online before print November 13, 2008

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(American Journal of Pathology. 2008;173:1806-1817.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080684

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 and Kazuo Sugamura^*

From the Departments of Microbiology and Immunology,^* Gastroenterology, Obstetrics and Gynecology, Cancer Science, and Pathology,^¶ Tohoku University Graduate School of Medicine, Sendai; the Department of Organ Anatomy,|| Yamaguchi University Graduate School of Medicine, Yamaguchi; the Laboratory for Animal Resources and Genetic Engineering,^** Center for Developmental Biology, Riken Kobe, Kobe; the Division of Immunology, Miyagi Cancer Center Research Institute, Natori; and the Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan

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.

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