Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system

Daisuke Yamada, Kenji Kawabe, Ikue Tosa, Shunpei Tsukamoto, Ryota Nakazato, Miki Kou, Koichi Fujikawa, Saki Nakamura, Mitsuaki Ono, Toshitaka Oohashi, Mari Kaneko, Shioi Go, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada

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3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number346
JournalCommunications Biology
Volume2
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

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    Yamada, D., Kawabe, K., Tosa, I., Tsukamoto, S., Nakazato, R., Kou, M., Fujikawa, K., Nakamura, S., Ono, M., Oohashi, T., Kaneko, M., Go, S., Hinoi, E., Yoneda, Y., & Takarada, T. (2019). Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system. Communications Biology, 2(1), [346]. https://doi.org/10.1038/s42003-019-0582-4