De Rosa Laura, Fasano Dominga, Zerillo Lucrezia, Valente Valeria, Izzo Antonella, Mollo Nunzia, Amodio Giuseppina, Polishchuk Elena, Polishchuk Roman, Melone Mariarosa Anna Beatrice, Criscuolo Chiara, Conti Anna, Nitsch Lucio, Remondelli Paolo, Pierantoni Giovanna Maria, Paladino Simona
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases, University of Campania Luigi Vanvitelli, Naples, Italy.
Front Genet. 2022 May 13;13:867989. doi: 10.3389/fgene.2022.867989. eCollection 2022.
Endosomal trafficking is essential for cellular homeostasis. At the crossroads of distinct intracellular pathways, the endolysosomal system is crucial to maintain critical functions and adapt to the environment. Alterations of endosomal compartments were observed in cells from adult individuals with Down syndrome (DS), suggesting that the dysfunction of the endosomal pathway may contribute to the pathogenesis of DS. However, the nature and the degree of impairment, as well as the timing of onset, remain elusive. Here, by applying imaging and biochemical approaches, we demonstrate that the structure and dynamics of early endosomes are altered in DS cells. Furthermore, we found that recycling trafficking is markedly compromised in these cells. Remarkably, our results in 18-20 week-old human fetal fibroblasts indicate that alterations in the endolysosomal pathway are already present early in development. In addition, we show that overexpression of the polyphosphoinositide phosphatase synaptojanin 1 (Synj1) recapitulates the alterations observed in DS cells, suggesting a role for this lipid phosphatase in the pathogenesis of DS, likely already early in disease development. Overall, these data strengthen the link between the endolysosomal pathway and DS, highlighting a dangerous liaison among Synj1, endosomal trafficking and DS.
内体运输对于细胞内稳态至关重要。处于不同细胞内途径的交汇点，内溶酶体系统对于维持关键功能和适应环境至关重要。在唐氏综合征（DS）成年个体的细胞中观察到内体区室的改变，这表明内体途径的功能障碍可能导致DS的发病机制。然而，损伤的性质和程度以及发病时间仍然难以捉摸。在这里，通过应用成像和生化方法，我们证明早期内体的结构和动力学在DS细胞中发生了改变。此外，我们发现这些细胞中的再循环运输明显受损。值得注意的是，我们在18 - 20周龄人类胎儿成纤维细胞中的结果表明，内溶酶体途径的改变在发育早期就已经存在。此外，我们表明多磷酸肌醇磷酸酶突触素1（Synj1）的过表达重现了在DS细胞中观察到的改变，这表明这种脂质磷酸酶在DS的发病机制中起作用，可能在疾病发展的早期阶段就起作用。总体而言，这些数据加强了内溶酶体途径与DS之间的联系，突出了Synj1、内体运输和DS之间的危险关联。
