TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA binding protein critical for regulating gene expression, including transcription, splicing, mRNA stability, and protein translation. Aggregation of pathological TDP-43 proteins in the cytoplasm of neurons and glial cells appears to be a common feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as frontotemporal dementia (FTD), contributing to motor neuron degeneration and clinical symptoms. Downregulation of TDP-43 expression to prevent or reduce the formation of pathological aggregates is a potential therapeutic approach for treating TDP-43-related diseases. However, therapeutic strategies to reduce TDP-43 aggregation face significant challenges, as the downregulation of TDP-43 must balance the need to maintain its normal functions, which are essential for RNA metabolism and cellular homeostasis. In this study, we developed novel polymeric nanovectors for the delivery of TDP-43 siRNAs in neuronal cells. These nanovectors were designed to provide adequate TDP-43 silencing to achieve the desired functional reduction of TDP-43 levels, thereby optimizing its impact on cellular functions. Our results demonstrate that the polymeric nanovector formulations effectively reduced TDP-43 mRNA and protein levels to an extent comparable to those observed with traditional lipid-based systems. Concurrently, the polymeric nanovectors exhibited an enhanced capacity to reduce stress granules (SG) formation and facilitate TDP-43-containing SG disassembly, while preserving its essential cellular functions. This study provides the first evidence that polymeric nanovectors may be a valuable tool for developing therapeutic strategies to treat TDP-43 protein diseases, such as ALS and FTD, by directly silencing TDP-43 to reduce its aggregation.

中文翻译：

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在神经元细胞中使用载有 siRNA 的聚合物纳米载体优化 TDP-43 沉默，用于治疗应用：平衡敲低和功能


TAR DNA 结合蛋白 43 （TDP-43） 是一种普遍表达的 DNA/RNA 结合蛋白，对调节基因表达（包括转录、剪接、mRNA 稳定性和蛋白质翻译）至关重要。病理性 TDP-43 蛋白在神经元和神经胶质细胞细胞质中的聚集似乎是肌萎缩侧索硬化症 （ALS） 和其他神经退行性疾病（如额颞叶痴呆 （FTD））的常见特征，导致运动神经元变性和临床症状。下调 TDP-43 表达以防止或减少病理聚集体的形成是治疗 TDP-43 相关疾病的潜在治疗方法。然而，减少 TDP-43 聚集的治疗策略面临重大挑战，因为 TDP-43 的下调必须平衡维持其正常功能的需求，这对 RNA 代谢和细胞稳态至关重要。在这项研究中，我们开发了用于在神经元细胞中递送 TDP-43 siRNA 的新型聚合物纳米载体。这些纳米载体旨在提供足够的 TDP-43 沉默，以实现 TDP-43 水平的预期功能降低，从而优化其对细胞功能的影响。我们的结果表明，聚合物纳米载体制剂有效降低了 TDP-43 mRNA 和蛋白质水平，其程度与传统基于脂质的系统相当。同时，聚合物纳米载体表现出增强的能力，可以减少应力颗粒 （SG） 的形成并促进含有 TDP-43 的 SG 分解，同时保留其基本的细胞功能。 这项研究提供了第一个证据，表明聚合物纳米载体可能是一种有价值的工具，通过直接沉默 TDP-43 以减少其聚集，从而成为开发治疗策略以治疗 TDP-43 蛋白质疾病（如 ALS 和 FTD）的有用工具。