title: Altered mTOR signalling in nephropathic cystinosis.
abstract: Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades.
authors.affiliation: Department of Growth and Regeneration, KU Leuven and University Hospitals Leuven, UZ Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Ivanova
authors.affiliation: Department of Growth and Regeneration, KU Leuven and University Hospitals Leuven, UZ Herestraat 49, 3000, Leuven, Belgium.|Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Lambertus P
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Department of Growth and Regeneration, KU Leuven and University Hospitals Leuven, UZ Herestraat 49, 3000, Leuven, Belgium.|Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Elmonem
authors.affiliation: Laboratory of Molecular and Cellular Signalling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.affiliation: Laboratory of Molecular and Cellular Signalling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Missiaen
authors.affiliation: Laboratory of Proteomics and Metabolomics, Children's Hospital and Research Institute "Bambino Gesù" IRCCS, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.affiliation: Department of Growth and Regeneration, KU Leuven and University Hospitals Leuven, UZ Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Djalila
authors.initials: D
authors.lastname: Mekahli
authors.affiliation: Laboratory of Molecular and Cellular Signalling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: Bultynck
authors.affiliation: Department of Growth and Regeneration, KU Leuven and University Hospitals Leuven, UZ Herestraat 49, 3000, Leuven, Belgium. elena.levtchenko@uzleuven.be.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Levtchenko
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism; D001343:Autophagy / Q000502:physiology; D002478:Cells, Cultured; D003543:Cysteamine / Q000378:metabolism; D003554:Cystinosis / Q000378:metabolism* / Q000473:pathology; D005198:Fanconi Syndrome / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D003543:Cysteamine; D000076222:Mechanistic Target of Rapamycin Complex 1