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Altered mTOR signalling in nephropathic cystinosis

Ekaterina A Ivanova1, Lambertus P van den Heuvel1,2, Mohamed A Elmonem1,3

  • 1Department of Growth and Regeneration, KU Leuven and University Hospitals Leuven, UZ Herestraat 49, 3000, Leuven, Belgium.

Journal of Inherited Metabolic Disease
|February 25, 2016
PubMed

Insights

Nephropathic cystinosis disrupts mammalian target of rapamycin complex 1 (mTORC1) signaling, causing abnormal lysosomal mTOR retention and delayed autophagy reactivation. This mTORC1 pathway dysfunction contributes to kidney tubule damage in cystinosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Lysosomes regulate autophagy through mammalian target of rapamycin complex 1 (mTORC1) activation.
  • Nephropathic cystinosis, a lysosomal storage disease, exhibits accumulation of autophagy markers.
  • Cystinosis results from cystinosin mutations, leading to kidney proximal tubule dysfunction and end-stage renal disease.

Purpose of the Study:

  • To investigate mTORC1 signaling in nephropathic cystinosis.
  • To determine the impact of cystinosin deficiency on mTORC1 pathway dynamics.
  • To explore potential therapeutic targets within mTORC1-dependent signaling cascades.

Main Methods:

  • Analysis of mTORC1 signaling in kidney proximal tubular cells from healthy donors and cystinosis patients.
  • Assessment of mTORC1 reactivation after starvation.
  • Evaluation of lysosomal mTOR localization during starvation.
  • Testing the efficacy of cysteamine treatment on mTORC1 signaling.

Main Results:

  • Cystinosis is associated with perturbed mTORC1 signaling.
  • Delayed reactivation of mTORC1 was observed after starvation in cystinotic cells.
  • Abnormal lysosomal retention of mTOR occurred during starvation.
  • Cysteamine treatment did not reverse these mTORC1 signaling alterations.

Conclusions:

  • Cystinosin deficiency impairs mTORC1 signaling and lysosomal function.
  • Altered mTORC1 signaling contributes to proximal tubular dysfunction in cystinosis.
  • Modulation of mTORC1 signaling presents a potential therapeutic strategy for cystinosis.

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