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.