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

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

doi:10.1038/s42003-019-0582-4

Daisuke Yamada, Yukio Yoneda + Show 13 more

Open Access

https://doi.org/10.1038/s42003-019-0582-4

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Journal: Communications Biology	Publication Date: Sep 18, 2019
Citations: 25	License type: open-access

Affiliation: Kanazawa University, Okayama University

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.

Highlights

The pathophysiological role of mammalian target of rapamycin complex 1 in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored
L-Gln indirectly activates mammalian target of rapamycin complex 1 (mTORC1) via the simultaneous influx of essential amino acids (EAAs) and efflux of L-Gln, which are regulated by Slc7a5 or Slc7a811,18,19
To identify solute carrier (Slc) family transporters, which are characterized by a positive regulatory role in mTORC1 activity and highly specific expression in the brain, we first compared mRNA copy numbers of systems A (Slc38a1, Slc38a2, and Slc38a4), N (Slc38a3 and Slc38a5), L (Slc7a5 and Slc7a8), and ASC (Slc1a5) transporter genes

Summary

Introduction

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. 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. Correspondence and requests for materials should be addressed to Functional defects in neurons cause neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and cerebrovascular disease These disorders are characterized by cellular damage and death in specific cerebral neurons, which are associated with physiological disabilities of patients, including tremor, paralysis, memory impairment, and cognitive dysfunction. MTOR inhibition exerts therapeutic effects in models of neurodegenerative disease[3], indicating the critical role of the mTOR-autophagy system in neuropathological disorders. Our data provide insights into the therapeutic strategies for patients with neuropathological diseases

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