C9orf72-mediated features, transcriptomic signatures, and translational studies for frontotemporal dementia and related disorders

项目摘要/摘要 我们试图进行深入的特征性研究，以揭示与临床病理变化相关的 患有额颞叶痴呆(FTD)和相关的神经退行性疾病，由在 C9orf72-SMCR8复合亚单位(C9orf72)。为此，我们将研究一系列神经解剖学 区域(例如，额叶皮质、颞叶皮质、运动皮质、脊髓和小脑)并跨越整个 额颞叶变性(FTLD)的频谱-FTD的神经病理诊断-TO 肌萎缩侧索硬化症(ALS)。对于每个地区，我们将评估C9orf72相关疾病的特征，如 C9orf72转录本、RNA焦点和二肽重复蛋白的AS水平(目标1)。此外，我们将使用 创新的靶向长读测序技术，用于测量该基因的大小、纯度和甲基化状态 扩展重复。此外，我们将进行全组织RNA测序，以检测 复杂的背景，基本上是抓拍(目标2)。这一数据将伴随着单核 转录数据，以获得基因表达水平，同时破译遇到的细胞多样性 中枢神经系统。由于C9orf72相关疾病中已有剪接缺陷的报道，我们将 结合短读和长读排序策略。长读测序数据的包含创建了 获得具有高精度剪接连接的全长转录组的机会，即使对于大型 成绩单。因此，这些结合起来的方法将使我们能够捕捉到 转录改变。通过我们深入的转录研究确定的热门词条将进一步 在我们广泛收集的临床和病理标本中进行了调查，并进行了潜在的测试 生物标志物。 综上所述，我们的详细检查将发现关键的地区和特定疾病的相似之处。 和/或差异，从而为更好地理解与 FTLD-ALS谱与疾病修饰物、可翻译生物标志物和治疗性物质的鉴定 目标。

PROJECT SUMMARY/ABSTRACT We seek to perform in-depth characterization studies to unravel the clinico-pathological variability associated with frontotemporal dementia (FTD) and related neurodegenerative diseases caused by an expanded repeat in the C9orf72-SMCR8 complex subunit (C9orf72). To this end, we will examine a range of neuroanatomical regions (e.g., frontal cortex, temporal cortex, motor cortex, spinal cord, and cerebellum) and span the full spectrum from frontotemporal lobar degeneration (FTLD) – a neuropathological diagnosis of FTD – to amyotrophic lateral sclerosis (ALS). For each region, we will assess features of C9orf72-linked diseases, such as levels of C9orf72 transcripts, RNA foci, and dipeptide repeat proteins (Aim 1). Moreover, we will use an innovative targeted long-read sequencing technology to measure the size, purity, and methylation status of the expanded repeat. Additionally, we will perform whole-tissue RNA sequencing to detect overall changes in a complex context, basically taking a snapshot (Aim 2). This data will be accompanied by single-nuclei transcriptomic data to acquire gene expression levels while deciphering the cellular diversity encountered in the central nervous system. Since splicing defects have been reported in C9orf72-related diseases, we will combine short- and long-read sequencing strategies. The inclusion of long-read sequencing data creates the opportunity to obtain the full-length transcriptome with highly accurate splice junctions, even for large transcripts. These combined approaches, therefore, will enable us to capture the entire landscape of transcriptomic changes. Top hits identified through our in-depth transcriptomic studies will be further investigated in our extensive collection of clinical and pathological specimens and tested as potential biomarkers. Taken together, our detailed examinations will uncover crucial region- and disease-specific similarities and/or differences, thus laying the foundation for improved understanding of the heterogeneity associated with the FTLD-ALS spectrum and the identification of disease modifiers, translatable biomarkers, and therapeutic targets.