The role of TDP-43 in oligodendrocytes

项目摘要 TDP-43是一种DNA/RNA结合蛋白，作为细胞RNA代谢的全局调节剂。 尽管TDP-43已经在神经元中关于神经变性疾病进行了广泛的研究，但其作用仍然是神经变性疾病的一部分。 在少突胶质细胞中的作用从未被提及。TDP-43功能的丧失，如核清除所示 TDP-43和蛋白质病，在少突胶质细胞已被观察到在许多神经退行性疾病， 表现为TDP-43的核清除和蛋白质病。大脑中成熟的少突胶质细胞 多种功能，包括产生髓鞘沿着神经元轴突，使跳跃 传导动作电位，为神经元提供代谢支持，调节细胞外K+ 体内平衡少突胶质细胞中的TDP-43功能障碍是否会破坏少突胶质细胞， 功能，并进一步有助于神经退行性疾病的病理生理学。 使用TDP-43基因缺失的转基因小鼠进行的初步研究， 少突胶质细胞显示TDP-43的缺失导致少突胶质细胞的结构异常， 可以在组织学上和通过体内双光子成像可视化。这些结构性变化涉及 存在异常的细胞质过程，形成环和缠结，并与 神经元胞体和血管。鉴于少突胶质细胞通常表现出对 在体内髓鞘形成中，只有神经元轴突与少突胶质细胞过程相关，这是有趣的， TDP-43的缺失导致少突胶质细胞识别环境和细胞的能力明显不足， 调节其目标选择性的线索。此外，少突胶质细胞特异性TDP-43缺失的小鼠 表现出自发性癫痫发作和加速死亡，伴有运动行为缺陷。 该提议的首要假设是少突胶质细胞中TDP-43的缺失破坏了 形态结构，目标选择性和功能，最终达到神经元 过度兴奋、神经变性和神经炎症。我将通过使用一个 少突胶质细胞中TDP-43的特异性遗传缺失，进行体内双光子成像， 广泛的组织学分析，并使用电生理学和视频脑电图。在目标1中，我将确定 TDP-43的选择性丢失影响少突胶质细胞和少突胶质细胞谱系细胞的动力学。在目标2中， 我将进一步描述和定义异常少突胶质细胞过程与 神经元细胞体和血管。最后，在目标3中，我将确定少突胶质细胞的功能障碍是否 由于TDP-43的缺失导致神经元兴奋性的改变、神经变性和 神经炎症这些研究将扩展我们对TDP-43的细胞类型特异性作用的认识， 少突胶质细胞中TDP-43功能障碍如何导致广泛的神经退行性疾病， 在神经元和少突胶质细胞中表现出TDP-43病理学。

PROJECT SUMMARY TDP-43 is a DNA/RNA binding protein that serves as the global regulator of cellular RNA metabolism. Although TDP-43 has been extensively studied in neurons with regard to neurodegenerative diseases, its role in oligodendrocytes has never been addressed. The loss of TDP-43 function, as indicated by nuclear clearance of TDP-43 and proteinopathy, in oligodendrocytes has been observed in many neurodegenerative diseases as indicated by nuclear clearance of TDP-43 and proteinopathy. Mature oligodendrocytes in the brain play a diverse set of functions, including generating myelin sheaths along neuronal axons to allow saltatory conduction of action potentials, providing metabolic support to neurons and modulating extracellular K+ homeostasis. It remains to be determined if TDP-43 dysfunction in oligodendrocytes disrupts oligodendrocyte function and further contributes to the pathophysiology of neurodegenerative diseases. Preliminary studies using transgenic mice with a genetic deletion of TDP-43 specifically in mature oligodendrocytes revealed that the loss of TDP-43 confers structural abnormalities in oligodendrocytes that may be visualized histologically and via in vivo two-photon imaging. These structural changes involved the presence of aberrant cytoplasmic processes that form loops and tangles and inappropriately associate with neuronal somata and blood vessels. Given that oligodendrocytes normally show an exquisite selectivity of myelination in vivo, where only neuronal axons associate with oligodendrocyte processes, it is intriguing how the loss of TDP-43 induces such dramatic deficits in oligodendrocytes to recognize environmental and cellular cues to regulate their target-selectivity. Furthermore, the mice with oligodendrocyte-specific TDP-43 deletion exhibited spontaneous seizures and accelerated death accompanied by deficits in motor behaviors. The overarching hypothesis of this proposal is that the loss of TDP-43 in oligodendrocytes disrupts morphological structures, target-selectivity and function that ultimately culminate in neuronal hyperexcitability, neurodegeneration and neuroinflammation. I will test this hypothesis by employing a specific genetic deletion of TDP-43 in oligodendrocytes, conducting in vivo two-photon imaging, performing extensive histological analyses, and using electrophysiology and video-EEG. In Aim 1, I will determine if the selective loss of TDP-43 affects the dynamics of oligodendrocytes and oligodendrocyte lineage cells. In Aim 2, I will further characterize and define the aberrant interaction of abnormal oligodendrocyte processes with neuronal cell bodies and blood vessels. Lastly, in Aim 3, I will determine if the dysfunction of oligodendrocytes due to the loss of TDP-43 results in the alteration of neuronal excitability, neurodegeneration and neuroinflammation. These studies will extend our knowledge about the cell-type specific role of TDP-43 and how TDP-43 dysfunction in oligodendrocytes contributes to a wide array of neurodegenerative diseases that exhibit TDP-43 pathology in neurons and oligodendrocytes.