Pathophysiology of genetically defined dementia and neurodegeneration: Defining therapeutic targets and pathways

项目总结/摘要 在题为“遗传性痴呆的病理生理学和 神经变性：定义治疗靶点和途径，“我们寻求推动 开发精确的药物来治疗与C9 ORF 72 G4 C2重复相关的衰弱性疾病 扩张，额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）最常见的遗传原因， 硬化症（ALS）。成功开发c9 FTD/ALS治疗需要精心策划的努力， 解决了药物发现过程的多个方面。为了改善患有以下疾病的患者的预后 c9 FTD/ALS，因此我们建议研究C9 ORF 72 G4 C2重复扩增的病理机制， 导致疾病，以及开发生物活性小分子和生物标志物。我们聚集了一个世界- 一流的团队结合了化学、神经学、细胞生物学、疾病建模和生物标志物方面的专业知识 这是一个密切合作并拥有所有资源的发展。我们的重大进展， 阐明扩展的G4 C2重复RNA转录物如何驱动毒性以及如何消除异常特征 与c9 FTD/ALS相关的研究导致发现：（i）由c9 FTD/ALS引起的新的病理机制。 G4 C2重复序列RNA或“c9 RAN蛋白”的积累， RNA;（ii）第一个已知影响c9 FTD/ALS疾病生物学的小分子;和（iii）第一个 类生物标志物研究新的治疗策略。 我们现在提出新颖和创新的化学方法来开发和优化化学探针 研究和缓解c9 FTD/ALS疾病机制。我们还提出了核质 转运缺陷可能是c9 FTD/ALS发病机制的一个基本途径。的确， 我们报道了核孔复合体和核质转运的破坏是导致细胞凋亡的主要原因。 果蝇和c9 FTD/ALS患者源性细胞模型中的神经变性。另外我们有 确定了聚（GP）c9 RAN蛋白不仅在c9 FTD/ALS的脑脊液（CSF）中可检出， 患者外周血淋巴细胞中也有。更重要的是，初步数据表明，CSF聚（GP） 水平与疾病的临床特征相关。因此，聚（GP）蛋白可能被证明在监测 疾病的严重程度和进展速度。基于这些令人兴奋的发现，我们的多学科研究 将提高对C9 ORF 72相关神经变性的理解，确定治疗靶点和潜力 临床和药效学生物标志物，并导致具有治疗作用的生物活性小分子的设计 潜力结合起来，我们的努力有望加速发现一种有效的治疗方法， c9FTD/ALS。

PROJECT SUMMARY/ABSTRACT In this P01 proposal entitled “Pathophysiology of genetically defined dementia and neurodegeneration: Defining therapeutic targets and pathways,” we seek to push forward the development of precise medicines to treat debilitating diseases associated with C9ORF72 G4C2 repeat expansions, the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Success in developing a treatment for c9FTD/ALS will require a well-orchestrated effort that addresses multiple aspects of the drug discovery process. To improve the prognosis for patients suffering from c9FTD/ALS, we thus propose to investigate pathomechanisms by which C9ORF72 G4C2 repeat expansions cause disease, as well as develop bioactive small molecules and biomarkers. We have assembled a world- class team combining expertise in chemistry, neurology, cell biology, disease modeling, and biomarker development that has worked closely together and has all resources in place. Our significant progress to elucidate how expanded G4C2 repeat RNA transcripts drive toxicity and how to abrogate aberrant features associated with c9FTD/ALS has led to the discovery of: (i) novel pathomechanisms caused by the accumulation of G4C2 repeat RNA or “c9RAN proteins” unconventionally translated from G4C2 repeat RNA; (ii) the first small molecule known to influence c9FTD/ALS disease biology; and (iii) a first-in- class biomarker to investigate new therapeutic strategies. We now bring forward novel and innovative chemical approaches to develop and optimize chemical probes to study and mitigate c9FTD/ALS disease mechanisms. We also present evidence that nucleocytoplasmic transport defects may be a fundamental pathway of c9FTD/ALS pathogenesis amenable to therapy. Indeed, we reported that disruption of the nuclear pore complex and nucleocytoplasmic transport is a primary cause of neurodegeneration in Drosophila and patient-derived cell models of c9FTD/ALS. In addition, we have established that poly(GP) c9RAN proteins are not only detectable in cerebrospinal fluid (CSF) from c9FTD/ALS patients but also in peripheral blood lymphocytes. What is more, preliminary data suggest that CSF poly(GP) levels associate with clinical features of disease. As such, poly(GP) proteins may prove useful in monitoring disease severity and rate of progression. Building upon these exciting findings, our multi-disciplinary studies will improve understanding of C9ORF72-related neurodegeneration, identify therapeutic targets and potential clinical and pharmacodynamic biomarkers, and lead to the design of bioactive small molecules with therapeutic potential. Combined, our efforts are anticipated to accelerate the discovery of an effective therapy for c9FTD/ALS.