The role of TDP-43 in oligodendrocytes

项目总结 TDP-43是一种DNA/RNA结合蛋白，是细胞RNA代谢的全球调节因子。 尽管TDP-43在神经元中与神经退行性疾病有关已被广泛研究，但它的作用 在少突胶质细胞中的作用从未被解决过。TDP-43功能的丧失，如核清除所示 在TDP-43和蛋白质病中，在许多神经退行性疾病中观察到少突胶质细胞，如 以TDP-43的核清除和蛋白病变为标志。大脑中成熟的少突胶质细胞扮演着 多种功能，包括沿着神经元轴突产生髓鞘以允许跳跃 动作电位传导、为神经元提供代谢支持和调节细胞外K+ 动态平衡。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仍有待确定 功能，并进一步有助于神经退行性疾病的病理生理学。 成熟期特异性TDP-43基因缺失转基因小鼠的初步研究 少突胶质细胞研究表明，TDP-43的缺失导致少突胶质细胞结构异常， 可以通过组织学和活体双光子成像进行可视化。这些结构性变化涉及 存在异常的细胞质突起，形成环状和缠结，并不适当地与 神经元体和血管。鉴于少突胶质细胞通常表现出精致的选择性 体内的髓鞘形成，只有神经元轴突与少突胶质细胞突起有关，这是如何有趣的 TDP-43的丢失导致少突胶质细胞在识别环境和细胞方面的巨大缺陷 调节它们的靶标选择性的线索。此外，少突胶质细胞特异性TDP-43缺失的小鼠 表现为自发性癫痫发作和加速死亡，并伴有运动行为障碍。 这一提议的主要假设是，少突胶质细胞中TDP-43的丢失破坏了 最终形成神经元的形态结构、靶点选择性和功能 过度兴奋、神经变性和神经炎症。我将通过使用一个 TDP-43在少突胶质细胞中的特异性基因缺失，进行体内双光子成像，进行 广泛的组织学分析，并使用电生理学和视频脑电。在目标1中，我将确定是否 TDP-43的选择性缺失影响少突胶质细胞和少突胶质细胞系细胞的动力学。在目标2中， 我将进一步描述和定义异常的少突胶质细胞突起与 神经元胞体和血管。最后，在目标3中，我将确定少突胶质细胞的功能障碍 由于TDP-43的丢失导致神经元兴奋性的改变，神经退行性变和 神经炎。这些研究将扩大我们对TDP-43和TDP-43在细胞类型中的特定作用的了解 少突胶质细胞中TDP-43功能障碍如何导致一系列神经退行性疾病 神经元和少突胶质细胞有TDP-43病理改变。

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.