# OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses
## 4 Discussion
All the decreases discussed in ApoER2/Reelin signaling found in human i3 neurons may contribute to understanding some of the neurological signs in LS; as mentioned patients with lissencephaly due to _RELIN_ mutations have a severe delay in cognitive development, hypotonia, and seizures [64; 110]. Moreover, substantial work has linked subtle alterations in ApoER2/Reelin signaling to neuropsychiatric disorders [111; 112; 113; 114]. For instance, the levels of Reelin are severely reduced in postmortem brain extracts from patients with chronic psychosis like schizophrenia and autism, behavioral disorders, and epilepsy [115; 116]. Regarding neurodegeneration, murine models of Alzheimer's disease (AD) show an early decline of Reelin in the hippocampus and cortex [117; 118], and human brains of AD patients have lower Reelin levels [117; 119]. Several studies have shown that Reelin prevents AD-related dysfunctions [57; 63]. At the same time, recently, a _RELIN-COLBOS_ variant, a gain of function of Reelin, was expressed in a male carrying a _PSEN1_ mutation responsible for autosomal dominant AD, delaying the appearance of AD symptoms in 30 years [120]. Besides Reelin, ApoER2 interacts with other ligands with different functions [121]. Remarkably, Apolipoprotein E4 (ApoE4) is an ApoE2 ligand strongly associated with the risk of AD [122]. One of the proposed mechanisms for the influence of ApoE4 on the pathogenesis of AD is the binding of ApoE4 to ApoER2, significantly decreasing its presence in the neuronal membrane, which in turn prevents the interaction of the receptor with Reelin at the synapse [123]. This does not occur if the ligand is ApoE2 or ApoE3 [123]. One of the most critical functions of Reelin at the synapse is the activation of the Src family kinases [124], which in turn phosphorylate the NMDA receptor, decreasing its recycling and strengthening the synapse [125; 126]. In this context, our results in LS suggest a similar mechanism of decreased ApoER2 in dendrites, which would partially explain the cognitive and learning problems LS patients face. Then, it is possible to hypothesize that LS patients expressing the ApoE4 isoform could be more prone to developing cognitive impairments. In this context, it was demonstrated that a reversal of the recycling blockage of ApoER2 restores Reelin regulation of synaptic function and signaling [62; 127]. Conversely, studies of several mutations of OCRL1 have shown that some patients with the same mutation responsible for LS can develop Dent-2 disease instead, which affects only the kidneys [6]. In this context, while heterozygous polymorphisms in _RELIN_ alone are insufficient to cause severe problems [128; 129; 130; 131], they may be sufficient to increase the severity of neurological issues in LS patients. In the same direction, transcriptomic analysis of iPSC-derived neuronal progenitors from LS patients shows an increase in Reelin mRNA [132], possibly needed as a compensatory mechanism to activate the signaling since our findings show a direct decrease in ApoER2 [133]. Our work supports the idea that the ApoER2/Reelin pathway is not entirely disrupted yet significantly affected in LS. Although the other Reelin receptor VLDL-R [57] has been less studied in terms of its endocytic trafficking than ApoER2, we cannot discard that its eventual recycling could be impaired by a direct effect of OCRL1 dysfunction at the endosomes as well as by a reduction of SNX17 in dendrites already discussed. These alterations would have an impact on the neurological development of LS patients. It is important to consider that we obtained our results from a complete KO of _OCRL_. However, there are a variety of mutations in OCRL1 causing LS, including nonsense, missense, frameshifts, splice sites, and gross genomic deletions of _OCRL_[6], and the alterations can occur in different domains of the protein [17; 18], adding complexity to the phenotype.