A cell-penetrating ester of the neural metabolite lanthionine ketimine stimulates autophagy through the mTORC1 pathway: Evidence for a mechanism of action with pharmacological implications for neurodegenerative pathologies

Neurobiology of Disease
Marni E Harris-WhiteKenneth Hensley

Abstract

Autophagy is a fundamental cellular recycling process vulnerable to compromise in neurodegeneration. We now report that a cell-penetrating neurotrophic and neuroprotective derivative of the central nervous system (CNS) metabolite, lanthionine ketimine (LK), stimulates autophagy in RG2 glioma and SH-SY5Y neuroblastoma cells at concentrations within or below pharmacological levels reported in previous mouse studies. Autophagy stimulation was evidenced by increased lipidation of microtubule-associated protein 1 light chain 3 (LC3) both in the absence and presence of bafilomycin-A1 which discriminates between effects on autophagic flux versus blockage of autophagy clearance. LKE treatment caused changes in protein level or phosphorylation state of multiple autophagy pathway proteins including mTOR; p70S6 kinase; unc-51-like-kinase-1 (ULK1); beclin-1 and LC3 in a manner essentially identical to effects observed after rapamycin treatment. The LKE site of action was near mTOR because neither LKE nor the mTOR inhibitor rapamycin affected tuberous sclerosis complex (TSC) phosphorylation status upstream from mTOR. Confocal immunofluorescence imaging revealed that LKE specifically decreased mTOR (but not TSC2) colocalization with LAMP2(+)...Continue Reading

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Citations

Dec 24, 2015·Frontiers in Physiology·Alla B SalminaMaik Gollasch
Jul 15, 2015·Neurobiology of Disease·D Allan Butterfield
Aug 16, 2016·Neurochemical Research·André Hallen, Arthur J L Cooper
Apr 12, 2018·Physiology·Maria A Gonzalez PorrasCarlos B Mantilla
Feb 13, 2019·International Journal of Molecular Sciences·Michiel Van BulckJose A Morales-Garcia
Jan 12, 2017·Toxins·Alessandra F PernaDiego Ingrosso
May 29, 2020·Molecular Neurobiology·Sachchida Nand RaiBrijesh Kumar Singh

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