@misc{oai:repo.qst.go.jp:00071607,
 author = {Ono, Maiko and Ji, Bin and Tokunaga, Masaki and Suhara, Tetsuya and Higuchi, Makoto and et.al and 小野 麻衣子 and 季 斌 and 徳永 正希 and 須原 哲也 and 樋口 真人},
 month = {May},
 note = {Here, we provide the first evidence that p62, ubiquitinated cargo receptor for selective autophagy, acts protectively against neuron death provoked by tau accumulation. In mice transgenic for P301S mutant human tau protein (P301S mice), autophagic activity in the hippocampus was higher than that in the brainstem, but this regional difference became unremarkable with aging, suggesting tau-induced impairment of autophagic processing in the hippocampus of old P301S mice. This could be associated with prominent neuronal loss observed in the hippocampus but not brainstem of old P301S mice. Genetic inactivation of p62 alone did not induce tau pathologies in mice, but P301S mice deficient in p62 (P301S/p62-KO mice) exhibited accelerated accumulation of soluble, phosphorylated tau as compared to P301S mice. Meanwhile, tau kinases (GSK-3 beta and Cdk5) remained unchanged, indicating that p62 serves autophagic clearance of pathologically phosphorylated tau. In vivo MRI demonstrated enhanced hippocampal atrophy in P301S/p62-KO mice relative to P301S mice. P301S mice progressively developed hippocampal aggresomes containing p62, ubiquitin and organelles but not phosphorylated tau. Notably, formation of these aggresomes was dramatically abolished in P301S/p62-KO mice, supporting the notion that p62-mediated packaging of ubiquitinated substrates such as damaged organelles and misfolded proteins except phosphor-tau into aggresomes is critical for neuronal survival. Finally, abundance of neurofibrillary tangles in P301S mice was not markedly altered by the deficiency of p62. Hence, p62 exerts neuroprotection against tau pathologies by eliminating nonfibrillar phospho-tau species primarily through selective autophagy and by sequestering other ubiquitinated components into aggresomes., XXVIth International Symposium on Cerebral Blood Flow, Metabolism and Function},
 title = {Pivotal roles of p62 and selective autophagy in tau deposition and consequent neurodegeneration revealed with tauopathy mouse models},
 year = {2013}
}