Down Syndrome Fetal Fibroblasts Display Alterations of Endosomal Trafficking Possibly due to SYNJ1 Overexpression

Frontiers in Genetics

Mariarosa Anna Beatrice Melone¹  Dominga Fasano¹  Paolo Remondelli²  Giuseppina Amodio²  Nunzia Mollo³  Valeria Valente³  Lucrezia Zerillo³  Giovanna Maria Pierantoni³  Laura De Rosa³  Antonella Izzo³  Anna Conti³  Simona Paladino³  Chiara Criscuolo⁴  Lucio Nitsch⁵  Roman Polishchuk⁶  Elena Polishchuk⁶ 

[1] Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases, University of Campania Luigi Vanvitelli, Naples, Italy;Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana, University of Salerno, Salerno, Italy;Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy;Department of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy;Institute of Experimental Endocrinology and Oncology “G. Salvatore,” National Research Council, Naples, Italy;Telethon Institute of Genetics and Medicine, Pozzuoli, Italy;

关键词: Down syndrome;    trisomy 21;    endosomal trafficking;    endolysosomal system;    synaptojanin 1;    membrane trafficking;   

DOI  :  10.3389/fgene.2022.867989

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown