The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia

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dc.contributor.authorCaracci, Mario O.
dc.contributor.authorPizarro, Hector
dc.contributor.authorAlarcon-Godoy, Carlos
dc.contributor.authorFuentealba, Luz M.
dc.contributor.authorFarfan, Pamela
dc.contributor.authorDe Pace, Raffaella
dc.contributor.authorSantibanez, Natacha
dc.contributor.authorCavieres, Viviana A.
dc.contributor.authorPastor, Tammy P.
dc.contributor.authorBonifacino, Juan S.
dc.contributor.authorMardones, Gonzalo A.
dc.contributor.authorMarzolo, Maria-Paz
dc.date.accessioned2025-01-20T17:07:52Z
dc.date.available2025-01-20T17:07:52Z
dc.date.issued2024
dc.description.abstractAdaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the mu 4 (AP4M1) subunit of AP-4. AP4E1- knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1-KO mice display increased co-localization of ApoER2 with Golgi markers. Furthermore, hippocampal neurons from Ap4e1-KO mice and AP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post -Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild -type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. This work thus establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.pneurobio.2024.102575
dc.identifier.eissn1873-5118
dc.identifier.issn0301-0082
dc.identifier.urihttps://doi.org/10.1016/j.pneurobio.2024.102575
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/90903
dc.identifier.wosidWOS:001180682400001
dc.language.isoen
dc.revistaProgress in neurobiology
dc.rightsacceso restringido
dc.subjectApoER2
dc.subjectReelin
dc.subjectAP-4
dc.subjectHereditary Spastic Paraplegia
dc.subjectGolgi
dc.subjectNeuron
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleThe Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia
dc.typeartículo
dc.volumen234
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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