PMID- 30808980
OWN - NLM
STAT- MEDLINE
DCOM- 20200915
LR  - 20200915
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Feb 26
TI  - Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje 
      cells.
PG  - 2799
LID - 10.1038/s41598-019-38730-4 [doi]
LID - 2799
AB  - 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.
FAU - Sakai, Yusuke
AU  - Sakai Y
AD  - Laboratory of Animal Resources, Center for Disease Biology and Integrative 
      Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, 
      Japan.
FAU - Kassai, Hidetoshi
AU  - Kassai H
AD  - Laboratory of Animal Resources, Center for Disease Biology and Integrative 
      Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, 
      Japan. kassai@m.u-tokyo.ac.jp.
FAU - Nakayama, Hisako
AU  - Nakayama H
AD  - Department of Neurophysiology, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, 113-0033, Japan.
AD  - Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, 
      Hiroshima University, Hiroshima, 734-8551, Japan.
AD  - Department of Physiology I (Neurophysiology), School of Medicine, Tokyo Women's 
      Medical University, Tokyo, 162-8666, Japan.
FAU - Fukaya, Masahiro
AU  - Fukaya M
AD  - Department of Anatomy, Kitasato University School of Medicine, Sagamihara, 
      252-0374, Japan.
FAU - Maeda, Tatsuya
AU  - Maeda T
AD  - Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, 
      113-0032, Japan.
AD  - Department of Biology, Hamamatsu University School of Medicine, Hamamatsu, 
      Shizuoka, 431-3192, Japan.
FAU - Nakao, Kazuki
AU  - Nakao K
AD  - Laboratory of Animal Resources, Center for Disease Biology and Integrative 
      Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, 
      Japan.
FAU - Hashimoto, Kouichi
AU  - Hashimoto K
AD  - Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, 
      Hiroshima University, Hiroshima, 734-8551, Japan.
FAU - Sakagami, Hiroyuki
AU  - Sakagami H
AD  - Department of Anatomy, Kitasato University School of Medicine, Sagamihara, 
      252-0374, Japan.
FAU - Kano, Masanobu
AU  - Kano M
AD  - Department of Neurophysiology, Graduate School of Medicine, The University of 
      Tokyo, Tokyo, 113-0033, Japan.
AD  - International Research Center for Neurointelligence (WPI-IRCN), The University of 
      Tokyo Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo, 
      113-0033, Japan.
FAU - Aiba, Atsu
AU  - Aiba A
AUID- ORCID: 0000-0002-8192-0778
AD  - Laboratory of Animal Resources, Center for Disease Biology and Integrative 
      Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, 
      Japan. aiba@m.u-tokyo.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190226
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Action Potentials/drug effects
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Behavior, Animal
MH  - Brain/pathology
MH  - Mechanistic Target of Rapamycin Complex 1/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred ICR
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Mitochondria/pathology
MH  - Purkinje Cells/cytology/metabolism/physiology
MH  - *Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - Tuberous Sclerosis Complex 1 Protein/deficiency/genetics
MH  - Tuberous Sclerosis Complex 2 Protein/deficiency/genetics
PMC - PMC6391425
COIS- The authors declare no competing interests.
EDAT- 2019/02/28 06:00
MHDA- 2020/09/17 06:00
PMCR- 2019/02/26
CRDT- 2019/02/28 06:00
PHST- 2018/09/10 00:00 [received]
PHST- 2018/11/19 00:00 [accepted]
PHST- 2019/02/28 06:00 [entrez]
PHST- 2019/02/28 06:00 [pubmed]
PHST- 2020/09/17 06:00 [medline]
PHST- 2019/02/26 00:00 [pmc-release]
AID - 10.1038/s41598-019-38730-4 [pii]
AID - 38730 [pii]
AID - 10.1038/s41598-019-38730-4 [doi]
PST - epublish
SO  - Sci Rep. 2019 Feb 26;9(1):2799. doi: 10.1038/s41598-019-38730-4.