{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T11:53:12Z","timestamp":1777204392860,"version":"3.51.4"},"reference-count":113,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T00:00:00Z","timestamp":1598313600000},"content-version":"vor","delay-in-days":237,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Foundation for Science and Technology"},{"name":"Norte Portugal Regional Operational Programme","award":["NORTE 2020"],"award-info":[{"award-number":["NORTE 2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Donnai-Barrow syndrome, a genetic disorder associated to LRP2 (low-density lipoprotein receptor 2\/megalin) mutations, is characterized by unexplained neurological symptoms and intellectual deficits. Megalin is a multifunctional endocytic clearance cell-surface receptor, mostly described in epithelial cells. This receptor is also expressed in the CNS, mainly in neurons, being involved in neurite outgrowth and neuroprotective mechanisms. Yet, the mechanisms involved in the regulation of megalin in the CNS are poorly understood. Using transthyretin knockout mice, a megalin ligand, we found that transthyretin positively regulates neuronal megalin levels in different CNS areas, particularly in the hippocampus. Transthyretin is even able to rescue megalin downregulation in transthyretin knockout hippocampal neuronal cultures, in a positive feedback mechanism via megalin. Importantly, transthyretin activates a regulated intracellular proteolysis mechanism of neuronal megalin, producing an intracellular domain, which is translocated to the nucleus, unveiling megalin C-terminal as a potential transcription factor, able to regulate gene expression. We unveil that neuronal megalin reduction affects physiological neuronal activity, leading to decreased neurite number, length and branching, and increasing neuronal susceptibility to a toxic insult. Finally, we unravel a new unexpected role of megalin in synaptic plasticity, by promoting the formation and maturation of dendritic spines, and contributing for the establishment of active synapses, both in in vitro and in vivo hippocampal neurons. Moreover, these structural and synaptic roles of megalin impact on learning and memory mechanisms, since megalin heterozygous mice show hippocampal-related memory and learning deficits in several behaviour tests. Altogether, we unveil a complete novel role of megalin in the physiological neuronal activity, mainly in synaptic plasticity with impact in learning and memory. Importantly, we contribute to disclose the molecular mechanisms underlying the cognitive and intellectual disabilities related to megalin gene pathologies.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa135","type":"journal-article","created":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T14:07:37Z","timestamp":1598364457000},"source":"Crossref","is-referenced-by-count":17,"title":["Neuronal megalin mediates synaptic plasticity\u2014a novel mechanism underlying intellectual disabilities in megalin gene pathologies"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5710-8819","authenticated-orcid":false,"given":"Jo\u00e3o R","family":"Gomes","sequence":"first","affiliation":[{"name":"Molecular Neurobiology Unit, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5011-352X","authenticated-orcid":false,"given":"Andrea","family":"Lobo","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Addiction Biology Group, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"}]},{"given":"Renata","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Unit, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}]},{"given":"Ana F","family":"Terceiro","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Addiction Biology Group, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"}]},{"given":"Susete","family":"Costelha","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Unit, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9929-6232","authenticated-orcid":false,"given":"Igor M","family":"Lopes","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Addiction Biology Group, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2548-6281","authenticated-orcid":false,"given":"Ana","family":"Magalh\u00e3es","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Addiction Biology Group, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"}]},{"given":"Teresa","family":"Summavielle","sequence":"additional","affiliation":[{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Addiction Biology Group, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-6899","authenticated-orcid":false,"given":"Maria J","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Unit, IBMC- Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2020,8,25]]},"reference":[{"key":"2020111604261507900_fcaa135-B1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/BF02820508","article-title":"Thyroxine binding to transthyretin Met 119. 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