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

Commun Biol. 2019 Sep 18;2:346. doi: 10.1038/s42003-019-0582-4. eCollection 2019.

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. Slc38a1 flox/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.

Keywords: Cell death in the nervous system; Neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System A / antagonists & inhibitors*
  • Amino Acid Transport System A / genetics
  • Amino Acid Transport System A / metabolism*
  • Animals
  • Autophagy / drug effects*
  • Cerebral Infarction / etiology
  • Cerebral Infarction / metabolism
  • Cerebral Infarction / pathology
  • Gene Expression
  • Genetic Loci
  • Genome
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotection
  • Neuroprotective Agents / pharmacology*
  • Organ Specificity
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Amino Acid Transport System A
  • Neuroprotective Agents
  • Slc38a1 protein, mouse
  • TOR Serine-Threonine Kinases