RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

RNA衰变是RNA动态平衡的重要组成部分。转录活性细胞，如神经元 已经开发出复杂的途径来调节RNA周转，并将这一过程与RNA合成平衡起来。 在最初的资助期间，我们发现个体细胞中的rna稳定性普遍异常。 患有肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)，涉及功能障碍 RNA清除途径在疾病发病机制中的作用。我们还表明，这些异常中的许多可能是 通过错误定位的核RNA结合蛋白和剪接因子TDP43的沉积来概括 95%的ALS患者和FTLD最常见的亚型(FTLD-TDP)的胞浆。在探索 TDP43沉积的下游后果，我们发现TDP43的积累优先影响 编码核糖体蛋白的mRNAs的剪接，导致过度的内含子保留和mRNAs 不稳定。根据这些结果，我们推测TDP43在肌萎缩侧索硬化症中错误定位和积聚 FTLD-TDP破坏了核糖体蛋白编码的mRNAs的稳定，影响了翻译和干扰 依赖主动翻译的RNA衰变机制，包括无义介导的RNA衰变(NMD)。 这些现象加在一起，预计会引发一种恶性循环，最终形成RNA和蛋白质 动态平衡失调，最终导致神经退化。目前的提案建立在最初资金的数据基础上 (I)阐明TDP43导致RNA失稳的机制；(Ii)对RNA的影响进行分类 蛋白质翻译和RNA动态平衡的不稳定；以及(Iii)评估两种药物的治疗潜力 有希望的遗传修饰剂，UPF1和YTHDF2，因为它们能够恢复RNA动态平衡和延长 ALS和FTLD-TDP人神经元模型的神经元存活。这些目标反映在我们的长期目标中 目的：明确TDP43在神经元和其他类型细胞中的功能，并利用这一信息 为肌萎缩侧索硬化症、FTLD-TDP和相关的TDP43蛋白病设计有效的神经保护策略。

RNA decay is a critical component of RNA homeostasis. Transcriptionally active cells such as neurons have developed intricate pathways for regulating RNA turnover and balancing this process with RNA synthesis. During the initial funding period, we uncovered widespread abnormalities in RNA stability in cells from individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), implicating dysfunctional RNA clearance pathways in disease pathogenesis. We also showed that many of these abnormalities could be recapitulated by the deposition of TDP43, a nuclear RNA binding protein and splicing factor that is mislocalized to the cytoplasm in >95% of ALS patients and the most common subtype of FTLD (FTLD-TDP). In probing the downstream consequences of TDP43 deposition, we discovered that TDP43 accumulation preferentially affects the splicing of mRNAs encoding ribosomal proteins, leading to excessive intron retention and mRNA destabilization. Based on these results, we hypothesize that TDP43 mislocalization and accumulation in ALS and FTLD-TDP destabilizes ribosomal protein-encoding mRNAs, compromising translation and interfering with RNA decay mechanisms that rely on active translation, including nonsense-mediated RNA decay (NMD). Together, these phenomena would be expected to trigger a vicious cycle culminating in RNA and protein dyshomeostasis, and eventually neurodegeneration. The current proposal builds on data from the initial funding period to (i) elucidate the mechanism of RNA destabilization by TDP43, (ii) categorize the impact of RNA destabilization on protein translation and RNA homeostasis; and (iii) evaluate the therapeutic potential of two promising genetic modifiers, UPF1 and YTHDF2, for their ability to restore RNA homeostasis and extend neuronal survival in human neuron models of ALS and FTLD-TDP. These goals are mirrored by our long-term objectives: to crystalize the function of TDP43 in neurons and other cell types, and harness this information to devise effective neuroprotective strategies for ALS, FTLD-TDP and related TDP43-proteinopathies.