TY - JOUR
T1 - Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system
AU - Yamada, Daisuke
AU - Kawabe, Kenji
AU - Tosa, Ikue
AU - Tsukamoto, Shunpei
AU - Nakazato, Ryota
AU - Kou, Miki
AU - Fujikawa, Koichi
AU - Nakamura, Saki
AU - Ono, Mitsuaki
AU - Oohashi, Toshitaka
AU - Kaneko, Mari
AU - Go, Shioi
AU - Hinoi, Eiichi
AU - Yoneda, Yukio
AU - Takarada, Takeshi
N1 - Funding Information:
This work was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas (26117507 and 16H01332) and for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) to T.T. from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. We thank Jamey D. Marth (University of California Santa Barbara, CA, USA) for providing Synapsin I-Cre mice. We thank the members of the Department of Animal Resources, Advanced Science Research Center, Okayama University and the Institute for Experimental Animals, Kanazawa University Advanced Science Research Center for their technical support.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1, Slc38a1) as a positive regulator of mTORC1 in neurons. Slc38a1flox/flox and Synapsin I-Cre mice were crossed to generate mutant mice in which Slc38a1 was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed that Slc38a1 deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.
AB - The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1, Slc38a1) as a positive regulator of mTORC1 in neurons. Slc38a1flox/flox and Synapsin I-Cre mice were crossed to generate mutant mice in which Slc38a1 was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed that Slc38a1 deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.
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U2 - 10.1038/s42003-019-0582-4
DO - 10.1038/s42003-019-0582-4
M3 - Article
C2 - 31925140
AN - SCOPUS:85073258536
SN - 2399-3642
VL - 2
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 346
ER -