ナカヤマ　ヒサコ   Hisako Nakayama   中山　寿子    所属   医学部 医学科    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells.
掲載誌名	正式名：Scientific Reports 略　 称：Sci Rep ISSNコード：20452322
掲載区分	国外
巻・号・頁	9(1),pp.2799
著者・共著者	Sakai Yusuke†, Kassai Hidetoshi, Nakayama Hisako, Fukaya Masahiro, Maeda Tatsuya, Nakao Kazuki, Hashimoto Kouichi, Sakagami Hiroyuki, Kano Masanobu, Aiba Atsu*
発行年月	2019/02
概要	Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolism. The importance of mTORC1 signaling in neuronal development and functions has been highlighted by its strong relationship with many neurological and neuropsychiatric diseases. Previous studies demonstrated that hyperactivation of mTORC1 in forebrain recapitulates tuberous sclerosis and neurodegeneration. In the mouse cerebellum, Purkinje cell-specific knockout of Tsc1/2 has been implicated in autistic-like behaviors. However, since TSC1/2 activity does not always correlate with clinical manifestations as evident in some cases of tuberous sclerosis, the intriguing possibility is raised that phenotypes observed in Tsc1/2 knockout mice cannot be attributable solely to mTORC1 hyperactivation. Here we generated transgenic mice in which mTORC1 signaling is directly hyperactivated in Purkinje cells. The transgenic mice exhibited impaired synapse elimination of climbing fibers and motor discoordination without affecting social behaviors. Furthermore, mTORC1 hyperactivation induced prominent apoptosis of Purkinje cells, accompanied with dysregulated cellular homeostasis including cell enlargement, increased mitochondrial respiratory activity, and activation of pseudohypoxic response. These findings suggest the different contributions between hyperactivated mTORC1 and Tsc1/2 knockout in social behaviors, and reveal the perturbations of cellular homeostasis by hyperactivated mTORC1 as possible underlying mechanisms of neuronal dysfunctions and death in tuberous sclerosis and neurodegenerative diseases.
DOI	10.1038/s41598-019-38730-4.
PMID	30808980