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Altered mTOR signalling in nephropathic cystinosis
Author(s) -
Ivanova Ekaterina A.,
Heuvel Lambertus P.,
Elmonem Mohamed A.,
De Smedt Humbert,
Missiaen Ludwig,
Pastore Anna,
Mekahli Djalila,
Bultynck Greet,
Levtchenko Ele.
Publication year - 2016
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-016-9919-z
Subject(s) - cystinosis , mtorc1 , cysteamine , fanconi syndrome , autophagy , pi3k/akt/mtor pathway , endocrinology , medicine , cystine , lysosomal storage disease , mechanistic target of rapamycin , kidney , biology , chemistry , cancer research , microbiology and biotechnology , signal transduction , disease , biochemistry , apoptosis , cysteine , enzyme
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.