Biological functions of glial TSPO in retina and brain models of the cholesterol storage disease Niemann-Pick type C (NPC)

神经胶质 TSPO 在胆固醇储存病 Niemann-Pick C 型 (NPC) 视网膜和脑模型中的生物学功能

• 批准号: 422187201
• 负责人: Professorin Dr. Antje Grosche
• 金额: --
• 依托单位: Standort München
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/422187201?language=en
• 关键词: Biological; functions; glial; TSPO; retina

Translocator protein 18 kDa (TSPO) is an integral protein of the outer mitochondrial membrane. Although its cellular functions are still debated, it is thought to play a role in neurosteroidogenesis, mitochondrial function, cell metabolism and neuroinflammation. In the central nervous system (CNS), TSPO expression is predominantly found in ependymal cells, microglia, and astrocytes, but its cellular expression pattern largely changes under neuroinflammatory and neurodegenerative conditions. For the retina, TSPO was reported to be a regulator of cholesterol and neurosteroid metabolism, so this part of the CNS can serve as an ideal and, most importantly, easy-to-study model to analyze cell-type-specific beneficial or detrimental effects of TSPO. In the healthy tissue, we detected the highest TSPO expression in Müller cells, the major macroglia in the retina. In contrast, in retinal pathologies, TSPO is strongly upregulated by reactive microglia. Our research project specifically aims to compare the function of glial TSPO in the retina with results from corresponding cell types in the brain. To determine the function of TSPO under physiological and neurodegenerative conditions, we selected the Niemann Pick type C (NPC) metabolic disease model with distinct retinal and brain pathology. This monogenetic disease – predominantly caused by the loss of NPC1 function – is characterized by cholesterol storage and metabolic defects. In our new microglia-specific NPC1 knockout model, we found early cell autonomous defects of microglia and massive upregulation of microglial TSPO. These microglial deficits resulted in pathological changes in other cell types such as astrocytes and neurons in various CNS regions, including the retina. Therefore, this model provides a unique opportunity to study the functions of TSPO in glial cholesterol transport, neurosteroidogenesis, neuroinflammation, and cellular metabolism in the retina and brain. Thus, we aim to clarify whether an increase in glial TSPO triggers protective or detrimental responses in the CNS and how this may contribute to neuropathology. In a translational approach, we will analyze the effect of TSPO loss on glial functions including cholesterol metabolism and neurosteroid biosynthesis in human retinal organoids with and without microglia under homeostatic and NPC conditions as done in our mouse model. These comparative studies of TSPO signaling cascades in murine and human glia will help to significantly expand our understanding of TSPO biology and its relevance to human disease.

转运蛋白18 kDa（TSPO）是线粒体外膜的一种整合蛋白。虽然其细胞功能仍有争议，但它被认为在神经类固醇生成，线粒体功能，细胞代谢和神经炎症中发挥作用。在中枢神经系统（CNS）中，TSPO表达主要存在于室管膜细胞、小胶质细胞和星形胶质细胞中，但其细胞表达模式在神经炎症和神经变性条件下发生很大变化。对于视网膜，据报道TSPO是胆固醇和神经类固醇代谢的调节剂，因此CNS的这一部分可以作为理想的，最重要的是，易于研究的模型来分析TSPO的细胞类型特异性有益或有害作用。在健康组织中，我们在视网膜中的主要大胶质细胞Müller细胞中检测到最高的TSPO表达。相反，在视网膜病变中，TSPO被反应性小胶质细胞强烈上调。我们的研究项目特别旨在比较视网膜中胶质TSPO的功能与大脑中相应细胞类型的结果。为了确定TSPO在生理和神经变性条件下的功能，我们选择了具有不同视网膜和脑病理学的Niemann Pick C型（NPC）代谢疾病模型。这种单基因疾病-主要由NPC 1功能丧失引起-以胆固醇储存和代谢缺陷为特征。在我们新的小胶质细胞特异性NPC 1敲除模型中，我们发现了小胶质细胞的早期细胞自主缺陷和小胶质细胞TSPO的大量上调。这些小胶质细胞缺陷导致其他细胞类型的病理变化，如各种CNS区域（包括视网膜）中的星形胶质细胞和神经元。因此，该模型提供了一个独特的机会来研究TSPO在神经胶质胆固醇转运，神经类固醇生成，神经炎症和视网膜和大脑中的细胞代谢中的功能。因此，我们的目的是澄清是否增加胶质TSPO触发保护性或有害的反应，在中枢神经系统和这可能有助于神经病理学。在翻译方法中，我们将分析TSPO损失对神经胶质功能的影响，包括在稳态和NPC条件下具有和不具有小胶质细胞的人视网膜类器官中的胆固醇代谢和神经类固醇生物合成，如在我们的小鼠模型中所做的。这些比较研究TSPO信号级联在小鼠和人类神经胶质细胞将有助于显着扩大我们的理解TSPO生物学及其与人类疾病的相关性。