PDF(Pubmed)
Abstract：
Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS.
摘要：
Lowe综合征（LS）是一种罕见的X连锁疾病，以肾功能不全为特征，白内障,和几个中枢神经系统（CNS）异常。LS神经功能障碍的潜在机制尚不清楚，尽管它们具有一些类似于Reelin信号缺乏或功能障碍的表型特征，在中枢神经系统发育和神经元功能中起作用的相关途径。在这项研究中,我们研究了OCRL1的作用，OCRL基因编码的肌醇多磷酸5-磷酸酶，在LS中突变，关注其对人神经元细胞内体运输和受体再循环的影响。具体来说,我们测试了OCRL1缺乏在ApoER2/LRP8的运输和信号传导中的作用,ApoER2/LRP8是配体Reelin的受体.我们发现OCRL1的丢失会损害ApoER2的细胞内运输，导致受体表达降低和质膜水平降低。此外,缺乏OCRL1的人类神经元在ApoER2/Reelin诱导的反应中显示受损。我们的发现强调了OCRL1在调节ApoER2内体再循环及其对ApoER2/Reelin信号通路的影响中的关键作用。提供对LS神经系统表现潜在机制的见解。
