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

项目摘要/摘要 在这份题为《遗传性痴呆的病理生理学》的P01提案中 神经退行性变：确定治疗目标和途径，“我们寻求推动 治疗与C9ORF72 G4C2重复相关的衰弱疾病的精确药物的开发 扩张是额颞叶痴呆(FTD)和肌萎缩侧索硬化症最常见的遗传原因 硬化症(ALS)。成功开发c9FTD/ALS的治疗方法将需要精心策划的努力， 涉及药物发现过程的多个方面。改善慢性阻塞性肺疾病患者的预后 因此，我们建议研究C9ORF72 G4C2重复扩张的致病机制 导致疾病，以及发展生物活性小分子和生物标记物。我们已经组成了一个世界- 班级团队结合了化学、神经学、细胞生物学、疾病建模和生物标记物方面的专业知识 紧密合作并将所有资源到位的发展。我们在以下方面取得了重大进展 阐明扩增的G4C2重复RNA转录本如何驱动毒性以及如何消除异常特征 与C9FTD/ALS相关的研究导致发现：(I)新的致病机制由 非常规翻译自G4C2重复序列的G4C2重复序列RNA或“c9RAN蛋白”的积累 RNA；(Ii)已知的第一个影响C9FTD/ALS疾病生物学的小分子；以及(Iii)第一个... 研究新的治疗策略的生物标记物。 我们现在提出了新的和创新的化学方法来开发和优化化学探针 研究和缓解C9FTD/ALS的发病机制。我们还提出了核细胞质的证据 转运缺陷可能是C9FTD/ALS发病机制的基本途径。的确， 我们报告说，核孔复合体和核质运输的破坏是导致 果蝇的神经变性和C9FTD/ALS患者来源的细胞模型此外，我们还有 证实聚(GP)c9RAN蛋白不仅在C9FTD/ALS患者的脑脊液(CSF)中可检测到 患者外周血中也有淋巴细胞。更重要的是，初步数据表明，脑脊液聚(GP) 水平与疾病的临床特征有关。因此，多聚(GP)蛋白可能被证明在监测 疾病的严重程度和进展速度。在这些令人兴奋的发现的基础上，我们的多学科研究 将提高对C9ORF72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。联合起来，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.