Molecular and cellular characterization of SMN-mediated U7 snRNP assembly

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是一种运动神经元疾病，目前尚无有效治疗方法。SMA是由进化上保守和普遍表达的运动神经元存活（SMN）蛋白水平降低引起的。SMN与其他几种核心蛋白一起形成大分子SMN复合物，其在核糖核蛋白（RNP）的组装中起作用。虽然SMN被认为组装各种RNP，但迄今为止，其唯一充分表征的功能是组装剪接体小核核糖核蛋白（snRNP），这是真核mRNA剪接机制的关键组分。SMN依赖性RNA剪接途径的破坏尚不能解释SMA的潜在疾病机制，突出了识别由SMN控制的其他途径的重要性。我们的初步工作鉴定了U 7 snRNP的组装-复制依赖性组蛋白mRNA的3 '端加工所需的RNP因子-在体内为SMN依赖性。由于SMN缺乏而导致的该途径的破坏导致组蛋白合成的失调，对下游细胞过程具有潜在的有害影响。该研究项目旨在建立在这些发现的基础上，以确定SMN介导的U 7 snRNP生物发生的关键RNA和蛋白质决定因素，以及确定U 7功能障碍引起的组蛋白合成改变是否有助于SMN缺乏引起的细胞表型，包括运动神经元存活。总之，该项目旨在表征SMA被破坏的SMN依赖性RNA途径，并且可能具有有害的细胞后果，对疾病的病因学具有重要意义。! ! 公共卫生相关性：脊髓性肌萎缩症（SMA）是一种儿童神经退行性疾病，目前尚无有效的治疗方法，是由运动神经元存活蛋白（SMN）缺乏引起的。为了确定有效SMA治疗的靶点，必须表征由SMN控制的基本生物学途径。该项目旨在表征在疾病中被破坏的新型SMN依赖性途径，以揭示新的疾病机制，这可能为SMA治疗靶向提供新的途径。

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a motor neuron disease for which no effective treatment is currently available. SMA is caused by reduced levels of the evolutionarily conserved and ubiquitously expressed survival of motor neuron (SMN) protein. SMN together with several other core proteins forms the macromolecular SMN complex, which functions in the assembly of ribonucleoproteins (RNPs). While SMN is believed to assemble a variety of RNPs, to date its only well-characterized function is in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), critical components of the eukaryotic mRNA splicing machinery. Disruption of an SMN-dependent RNA splicing pathway has not yet been able to explain the underlying disease mechanisms in SMA, highlighting the significance of identifying additional pathways controlled by SMN. Our preliminary work identifies the assembly of the U7 snRNP - a RNP factor required for 3'-end processing of replication dependent histone mRNAs - as SMN-dependent in vivo. Disruption of this pathway due to SMN deficiency causes deregulation of histone synthesis with potentially detrimental effects on downstream cellular processes. This research project aims to build on these findings to identify the critical RNA and protein determinants of SMN-mediated U7 snRNP biogenesis, as well as to determine whether altered histone synthesis caused by U7 dysfunction contributes to cellular phenotypes caused by SMN deficiency, including motor neuron survival. Taken together, this project aims to characterize an SMN-dependent RNA pathway that is disrupted is SMA and may have deleterious cellular consequences with important implications in etiology of the disease. ! ! PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy (SMA), a childhood neurodegenerative disease for which no effective treatment is currently available, is caused by a deficiency in the survival motor neuron (SMN) protein. To identify targets for effective SMA therapeutics, it is essential to characterize the fundamental biological pathways controlled by SMN. This project aims to characterize a novel SMN-dependent pathway that is disrupted in the disease in an effort to reveal novel disease mechanisms, which may provide new avenues for SMA therapeutic targeting.