Neuronal megalin mediates synaptic plasticity-a novel mechanism underlying intellectual disabilities in megalin gene pathologies.
Neuronal megalin mediates synaptic plasticity-a novel mechanism underlying intellectual disabilities in megalin gene pathologies.
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DOI：
10.1093/braincomms/fcaa135
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发表时间：
2020
影响因子：
4.8
通讯作者：
Saraiva MJ
中科院分区：
文献类型：
--
作者：
Gomes JR;Lobo A;Nogueira R;Terceiro AF;Costelha S;Lopes IM;Magalhães A;Summavielle T;Saraiva MJ
Donnai-Barrow综合征是一种与LRP2(低密度脂蛋白受体2/megalin)突变相关的遗传性疾病，其特征是无法解释的神经症状和智力缺陷。巨蛋白是一种多功能的胞内清除细胞表面受体，主要在上皮细胞中表达。该受体在中枢神经系统也有表达，主要在神经元中表达，参与轴突生长和神经保护机制。然而，对中枢神经系统中巨蛋白的调控机制知之甚少。通过对巨蛋白配体--转甲状腺激素基因敲除小鼠的研究，我们发现，在不同的中枢神经系统区域，尤其是在海马区，反式甲状腺激素对神经元的巨蛋白水平有积极的调节作用。在转基因海马神经细胞培养中，促甲状腺激素甚至能够通过促甲状腺激素的正反馈机制，挽救促甲状腺激素基因敲除的海马神经元细胞中促甲状腺激素蛋白的下调。重要的是，转甲状腺素激活了神经元巨蛋白在细胞内的蛋白分解机制，产生一个胞内结构域，该结构域被移位到细胞核，揭示了巨蛋白C末端作为一个潜在的转录因子，能够调节基因的表达。我们揭示了神经元巨蛋白的减少会影响神经元的生理活动，导致轴突数量、长度和分支减少，并增加神经元对毒性损伤的敏感性。最后，我们揭示了megalin在突触可塑性中的一个新的意想不到的作用，它通过促进树突棘的形成和成熟，并在体外和体内海马神经元中帮助建立活跃的突触。此外，巨蛋白的这些结构和突触作用影响了学习和记忆机制，因为巨蛋白杂合子小鼠在几项行为测试中显示出与海马区相关的记忆和学习缺陷。综上所述，我们揭示了megalin在生理神经元活动中的全新作用，主要是在突触可塑性中对学习和记忆的影响。重要的是，我们有助于揭示与巨蛋白基因病理相关的认知和智力障碍的分子机制。唐奈-巴罗综合征是一种与巨蛋白突变有关的遗传性疾病，表现出无法解释的智力缺陷。我们描述了megalin，一种多功能的受体，通过其配体TTR来调节神经元的活动和存活。此外，我们揭示了巨蛋白在突触可塑性中的一个新角色，对学习和记忆的影响，解释了所描述的智力障碍。
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. Donnai-Barrow syndrome, genetic disorder linked to megalin mutations, shows unexplained intellectual deficits. We describe that megalin, a multifunctional receptor, via its ligand TTR, regulates neuronal activity and survival. Additionally, we unravel a novel role of megalin in synaptic plasticity, with impact on learning and memory, explaining the described intellectual disabilities.
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影响因子：
4.7
作者：
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通讯作者：
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DOI：
10.1073/pnas.0712197105
发表时间：
2008-02-19
影响因子：
11.1
作者：
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缺乏内皮梅加林的小鼠的肥胖和神经炎症表型。
影响因子：
9.3
作者：
Bartolome F;Antequera D;Tavares E;Pascual C;Maldonado R;Camins A;Carro E
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