Abstract：
Mutations of the human TRAFFICKING PROTEIN PARTICLE COMPLEX SUBUNIT 9 (TRAPPC9) cause a neurodevelopmental disorder characterised by microcephaly and intellectual disability. Trappc9 constitutes a subunit specific to the intracellular membrane-associated TrappII complex. The TrappII complex interacts with Rab11 and Rab18, the latter being specifically associated with lipid droplets (LDs). Here we used non-invasive imaging to characterise Trappc9 knock-out (KO) mice as a model of the human hereditary disorder. KOs developed postnatal microcephaly with many grey and white matter regions being affected. In vivo magnetic resonance imaging (MRI) identified a disproportionately stronger volume reduction in the hippocampus, which was associated with a significant loss of Sox2-positive neural stem and progenitor cells. Diffusion tensor imaging indicated a reduced organisation or integrity of white matter areas. Trappc9 KOs displayed behavioural abnormalities in several tests related to exploration, learning and memory. Trappc9-deficient primary hippocampal neurons accumulated a larger LD volume per cell following Oleic Acid stimulation, and the coating of LDs by Perilipin-2 was much reduced. Additionally, Trappc9 KOs developed obesity, which was significantly more severe in females than in males. Our findings indicate that, beyond previously reported Rab11-related vesicle transport defects, dysfunctions in LD homeostasis might contribute to the neurobiological symptoms of Trappc9 deficiency.
摘要：
人类运动蛋白质颗粒复合物子单元9(TRAPPC9)的突变引起以小头畸形和智力障碍为特征的神经发育障碍。Trappc9构成对胞内膜相关的TrappII复合物具有特异性的亚基。TrappII复合物与Rab11和Rab18相互作用，后者与脂滴（LD）特异性相关。在这里，我们使用非侵入性成像来表征Trappc9敲除（KO）小鼠作为人类遗传性疾病的模型。KOs出现了产后小头畸形，许多灰质和白质区域受到影响。体内磁共振成像（MRI）发现海马的体积减少不成比例，这与Sox2阳性神经干细胞和祖细胞的大量丢失有关。扩散张量成像显示白质区域的组织或完整性降低。Trappc9KOs在与探索有关的几项测试中表现出行为异常，学习和记忆。油酸刺激后，Trappc9缺陷的原代海马神经元每个细胞积累了更大的LD体积，Perilipin-2对LD的涂层大大减少。此外,Trappc9KOs患上了肥胖症，女性比男性严重得多。我们的研究结果表明,除了先前报道的Rab11相关的囊泡运输缺陷，LD稳态的功能障碍可能导致Trappc9缺乏症的神经生物学症状。
