Hisako Nakayama
   Department   School of Medicine, School of Medicine
   Position   Associate Professor
Article types Original article
Language English
Peer review Peer reviewed
Title Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells.
Journal Formal name：Scientific Reports
Abbreviation：Sci Rep
ISSN code：20452322
Domestic / ForeginForegin
Volume, Issue, Page 9(1),pp.2799
Author and coauthor Sakai Yusuke†, Kassai Hidetoshi, Nakayama Hisako, Fukaya Masahiro, Maeda Tatsuya, Nakao Kazuki, Hashimoto Kouichi, Sakagami Hiroyuki, Kano Masanobu, Aiba Atsu*
Publication date 2019/02
Summary 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