Jamalpoor Amer, Othman Amr, Levtchenko Elena N, Masereeuw Rosalinde, Janssen Manoe J
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584, CG, Utrecht, The Netherlands.
Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & KU Leuven, Leuven, Belgium.
Trends Mol Med. 2021 Jul;27(7):673-686. doi: 10.1016/j.molmed.2021.04.004. Epub 2021 May 8.
Nephropathic cystinosis is a severe, monogenic systemic disorder that presents early in life and leads to progressive organ damage, particularly affecting the kidneys. It is caused by mutations in the CTNS gene, which encodes the lysosomal transporter cystinosin, resulting in intralysosomal accumulation of cystine. Recent studies demonstrated that the loss of cystinosin is associated with disrupted autophagy dynamics, accumulation of distorted mitochondria, and increased oxidative stress, leading to abnormal proliferation and dysfunction of kidney cells. We discuss these molecular mechanisms driving nephropathic cystinosis. Further, we consider how unravelling molecular mechanisms supports the identification and development of new strategies for cystinosis by the use of small molecules, biologicals, and genetic rescue of the disease in vitro and in vivo.
肾病性胱氨酸病是一种严重的单基因全身性疾病，在生命早期出现并导致进行性器官损伤，尤其影响肾脏。它由CTNS基因突变引起，该基因编码溶酶体转运蛋白胱氨酸转运体，导致胱氨酸在溶酶体内蓄积。最近的研究表明，胱氨酸转运体的缺失与自噬动力学紊乱、畸形线粒体的积累以及氧化应激增加有关，从而导致肾细胞异常增殖和功能障碍。我们讨论了驱动肾病性胱氨酸病的这些分子机制。此外，我们还考虑了通过在体外和体内使用小分子、生物制剂以及对该疾病进行基因拯救来阐明分子机制如何支持胱氨酸病新策略的识别和开发。
