Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain.
Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
EMBO Rep. 2019 Nov 5;20(11):e48143. doi: 10.15252/embr.201948143. Epub 2019 Sep 18.
NPC is a neurodegenerative disorder characterized by cholesterol accumulation in endolysosomal compartments. It is caused by mutations in the gene encoding NPC1, an endolysosomal protein mediating intracellular cholesterol trafficking. Cognitive and psychiatric alterations are hallmarks in NPC patients pointing to synaptic defects. However, the role of NPC1 in synapses has not been explored. We show that NPC1 is present in the postsynaptic compartment and is locally translated during LTP. A mutation in a region of the NPC1 gene commonly altered in NPC patients reduces NPC1 levels at synapses due to enhanced NPC1 protein degradation. This leads to shorter postsynaptic densities, increased synaptic cholesterol and impaired LTP in NPC1 mice with cognitive deficits. NPC1 mediates cholesterol mobilization and enables surface delivery of CYP46A1 and GluA1 receptors necessary for LTP, which is defective in NPC1 mice. Pharmacological activation of CYP46A1 normalizes synaptic levels of cholesterol, LTP and cognitive abilities, and extends life span of NPC1 mice. Our results unveil NPC1 as a regulator of cholesterol dynamics in synapses contributing to synaptic plasticity, and provide a potential therapeutic strategy for NPC patients.
NPC 是一种神经退行性疾病，其特征是胆固醇在内溶酶体隔室中积累。它是由编码 NPC1 的基因突变引起的，NPC1 是一种参与细胞内胆固醇运输的内溶酶体蛋白。认知和精神改变是 NPC 患者的特征，表明存在突触缺陷。然而，NPC1 在突触中的作用尚未得到探索。我们发现 NPC1 存在于突触后隔室中，并在 LTP 期间局部翻译。NPC 患者中常见的 NPC1 基因区域的突变会由于 NPC1 蛋白降解增强而降低突触处的 NPC1 水平。这导致 NPC1 小鼠的突触后密度变短，突触胆固醇增加，LTP 受损，认知缺陷。NPC1 介导胆固醇的动员，并使 LTP 所必需的 CYP46A1 和 GluA1 受体在表面上进行传递，而 NPC1 小鼠中的这种传递是有缺陷的。CYP46A1 的药理学激活可使胆固醇、LTP 和认知能力的突触水平正常化，并延长 NPC1 小鼠的寿命。我们的结果揭示 NPC1 是调节突触中胆固醇动态的调节剂，有助于突触可塑性，并为 NPC 患者提供了一种潜在的治疗策略。
