# OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses
## 1 Introduction  
Lowe Syndrome (LS) is a rare genetic disorder linked to the X chromosome [1; 2; 3]. It manifests as a constellation of clinical features encompassing renal dysfunction, cataracts, and a spectrum of neurological abnormalities, including intellectual disabilities, seizures, and hypotonia [4; 5; 6; 7]. While the renal manifestations of LS have been extensively studied, the underlying mechanisms contributing to the neurologic dysfunction remain elusive [8; 9]. A limitation of the study of this condition has been the murine animal models for LS [8; 10; 11]; some of them do not show an apparent phenotype and do not recapitulate the complex neurological phenotype of the disease. Therefore, using relevant LS human cellular models such as neuronal cell lines and iPSCs-derived neurons is essential to find which processes are affected by this disease. Mutations in LS occur in _OCRL_[12; 13; 14; 15; 16; 17; 18], the gene encoding for the inositol polyphosphate 5-phosphatase OCRL1 [17; 19; 20]. Many of the functions of this protein have been investigated in kidney-derived cells [18; 21; 22; 23; 24] and fibroblasts [18; 25; 26; 27; 28]. OCRL1 participates in several cellular functions, from maintaining the compartmentalization of membrane domains to determining cell polarity, controlling cytoskeletal rearrangements, and regulating signaling pathways and intracellular trafficking [17; 18; 21; 22; 23; 24; 25]. Defects in the function of OCRL1 prompt the accumulation of its substrates, predominantly phosphatidylcholine1 inositol 4,5 biphosphate (PI(4,5)P\({}_{2}\)) [21; 29], disturbing actin polymerization and dynamics [21; 30; 31; 32]. In addition, LS cells show spreading defects [27; 33]. At the endylososomal level, OCRL1 has several functions; it binds to clathrin and to the adaptor complex AP-2 to allow the uncoating of vesicles [6], participates in maintaining autophagic flux [23] and regulateslysosome positioning to the cell periphery [34]. The dysregulation of OCRL1 halts various receptors, such as Megalin/LRP2, Transferrin Receptor (TfR), Epidermal Growth Factor Receptor (EGFR), and CI-Mannose-6-Phosphate Receptor (CI-MPR) in enlarged sorting endosomes characterized by the presence of the tethering protein Early Endosome Antigen 1 (EEA1); these receptors are accumulated and do not proceed to their destination to the plasma membrane in the recycling pathway, to late endosomes for degradation, or the Golgi complex in the retrograde pathway [21; 27]. ApoER2/LRP8 belongs to the Low-Density Lipoprotein Receptor-Related Protein (LRP) family as Megalin [35]. ApoER2 is predominantly expressed in the brain [36; 37] but is also found in the peripheral nervous system [38] and endocrine organs [39]. At a cellular level, ApoE2 is constitutively internalized [40]. From here, ApoER2 is recognized by endosomal sorting protein 17 (SNX17), which leads the recycling of ApoER2 either by Rab11 recycling endosomes or directly to the plasma membrane, escaping lysosomal degradation [41]. The primary role of ApoER2 in the central nervous system (CNS) is as a receptor for Reelin, a secreted glycoprotein mainly involved in brain development, learning, and memory [42]. Reelin binds to ApoER2, inducing its clustering and the recruitment and phosphorylation of the adaptor protein Dab1 [42; 43]. Then, PI-3K is activated, followed by the activation of AKT [44; 45] and Rho GTPases as Rac1 and Cdc42 [38; 46], required for the orientation and migration of multipolar cortical neurons, Golgi deployment [47; 48], and growth and branching of dendrites [45; 49]. ApoER2/Reelin also participates in the regulation of gene expression through the activation (phosphorylation) of ERK and CREB [50; 51], with a relevant role of the ApoER2 intracellular domain [52; 53], which acts on specific enhancers forming a complex with pCREB [50]. The absence or reduction of the ApoER2/Reelin signaling pathway has been associated with cognitive dysfunction [54], neuropsychiatric disorders [55; 56], and neurodegenerative diseases [57].