RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

RNA衰变是RNA稳态的关键组成部分。转录活性细胞，如神经元 已经开发了复杂的途径来调节RNA周转并平衡这一过程与RNA合成。 在最初的资助期间，我们发现了个体细胞中RNA稳定性的普遍异常， 患有肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）， 疾病发病机制中的RNA清除途径。我们还表明，许多这些异常可能是 由沉积的TDP 43概括，TDP 43是一种核RNA结合蛋白和错误定位的剪接因子 在>95%的ALS患者和最常见的FTLD亚型（FTLD-TDP）中，在探索 TDP 43沉积的下游后果，我们发现TDP 43积累优先影响 编码核糖体蛋白的mRNA的剪接，导致过量的内含子保留和mRNA 不稳定基于这些结果，我们假设TDP 43在ALS中的错误定位和积累 FTLD-TDP使核糖体蛋白编码mRNA不稳定，损害翻译并干扰 依赖于主动翻译的RNA衰变机制，包括无义介导的RNA衰变（NMD）。 这些现象加在一起，预计将引发一个恶性循环，最终导致RNA和蛋白质 内分泌失调最终导致神经退行性变目前的提案是基于最初供资的数据 阶段，以（i）阐明由TDP 43引起的RNA不稳定的机制，（ii）对RNA的影响进行分类， 蛋白质翻译和RNA稳态的不稳定性;和（iii）评估两种药物的治疗潜力 UPF 1和YTHDF 2是很有前途的遗传修饰剂，因为它们能够恢复RNA稳态并延长 在ALS和FTLD-TDP的人神经元模型中的神经元存活。这些目标反映在我们的长期目标中。 目的：明确TDP 43在神经元和其他细胞类型中的功能，并利用这些信息， 为ALS、FTLD-TDP和相关的TDP 43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.