INTRACELLULAR TRAFFICKING DEFECTS UNDERLY DYSFUNCTIONS IN REELIN SIGNALING; IMPLICATIONS FOR RARE-GENETIC DISEASES AFFECTING THE CENTRAL NERVOUS SYSTEM

Reelin is a secreted glycoprotein that regulates brain´s development, function, and plasticity. Reelin and its receptors, ApoER2 and VLDLR, have critical roles in neuroprotection in diseases like Alzheimer´s and Parkinson´s. Decreased Reelin is found in neuropsychiatric disorders, including depression, schizophrenia, and autistic spectrum disorder and causes brain defects like microcephaly and thin corpus callosum. 

ApoER2, is internalized in clathrin-mediated pathway and recycled to the plasma membrane from early endosomes. Here we present our recent and ongoing work on the role the endosomal recycling and the biosynthetic and polarized trafficking of ApoER2, pointing out on how these routes, when are affected in specific disease conditions, impact in a significant way, the neuronal responses to Reelin. 

In its biosynthetic traffic to the neuronal surface, ApoER2 interacts with adaptor complex AP-4, mutated in Hereditary Spastic Paraplegia (HSP-AP4). AP-4 related type of HSP is an autosomal recessive rare condition characterized by neonatal hypotonia, progressive spasticity, developmental delay, and seizures. AP-4 participates in the recognition of membrane proteins exiting the Golgi apparatus, defining their polarized distribution. In AP-4 deficient mouse and human neurons, ApoER2 axonal distribution and total levels are significantly decreased, affecting relevant Reelin responses.

Lowe Syndrome (LS), a rare X-linked genetic disease characterized by renal, ocular, and neurological manifestations including mental retardation, behavioral disorders, repetitive behaviors, and stereotypies. Mutations OCRL the gene encoding the phosphatase OCRL1 are responsible for this syndrome. OCRL1 indirect roles are the regulation of intracellular trafficking and protein sorting of receptors at the endosomal compartment. Whereas most of the studies in LS have been performed in kidney cells, little is known in neurons, in which we found that OCRL1 deficiency affects ApoER2 endosomal traffic and increases the receptor degradation. These changes were reflected in reductions in Reelin-induced responses in human neurons. 

The stablishment of HSP and LS cellular models allowed to find significant alterations in ApoER2/Reelin signaling. We propose that in conditions like HSP and LS or related with them, relevant functions of Reelin signaling associated with neurodevelopment and learning and memory processes are affected and would explain part of the patients´neurologic phenotypic features found in these diseases.