Poly(ADP-ribose) promotes the condensation and toxicity of C9orf72 arginine-rich dipeptide repeat proteins

C9orf72基因中GGGGCC六核苷酸重复序列的扩展是最常见的遗传原因 肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)，两种毁灭性的神经退行性变 没有有效治疗的疾病。我们已经证明，扩展的重复序列的转录本经历了 非传统的翻译模式，导致产生五个二肽重复蛋白(Dprs)。我们的 研究小组和其他人证实，dprs形成遍及中枢神经系统的神经元包涵体。 C9orf72相关的ALS和FTD患者(“C9ALS/FTD”)。这种神经病理的鉴定 霍尔马克揭示了可能的疾病机制，以及我们对人类dprs的系统评估。 组织以及它们在小鼠和其他临床前模型中的评估表明，富含精氨酸的dprs， Poly(GR)和Poly(PR)尤其有毒。我们的数据进一步表明，这种毒性至少部分源于， 从这些DPR蛋白与调节必需的蛋白质的共缩合和/或共聚集 细胞功能，如应激颗粒生物学和核质运输。我们还表明， Poly(GR)聚集诱导TDP-43病理，这是c9ALS/FTD和大多数的另一个显著特征 散发性肌萎缩侧索硬化症和FTD病例。然而，由于Poly(GR)和Poly(PR)与200多个 内源性蛋白质，它们可能会对一系列细胞功能产生不利影响--一系列研究 这值得关注。同样重要的是确定调节Poly(GR)和 聚(PR)的缩合和聚集，以及它们与其他蛋白质的相互作用。因此值得注意的是，我们的 初步数据显示，聚(ADP-核糖)(PAR)促进聚(GR)和聚(PR)缩合，以及 在体外增强它们与疾病相关蛋白的共凝聚或共聚集。此外，我们 观察到降低PAR抑制了多聚(GR)或多聚(PR)介导的果蝇神经变性。在……里面 根据这些令人兴奋的发现，我们假设PAR介导了富含精氨酸的聚集和毒性。 Dprs及其结合的蛋白质。因此，提议的项目的目标是确定如何 确实是这样的。为此，我们将确定与PAR依赖的聚(GR)或聚(PR)相互作用的蛋白质 时尚，并研究PAR对富含精氨酸的DPR聚集和毒性的贡献 临床前模型和C9orf72扩张型携带者的脑组织。总体而言，通过利用多样化的专业知识 在我们的团队成员中，我们努力阐明par和富含精氨酸的dpr蛋白在c9als/ftd中的作用。 发病机制，从而发现新的治疗靶点，加快有效治疗的开发 用于C9ALS/FTD。

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with no effective treatment. We have shown that transcripts of the expanded repeat undergo an unconventional mode of translation, resulting in the production of five dipeptide repeat proteins (DPRs). Our group and others demonstrated that DPRs form neuronal inclusions throughout the central nervous system of patients with C9orf72-associated ALS and FTD (“c9ALS/FTD”). The identification of this neuropathological hallmark shed new light on possible disease mechanisms, and our systematic assessment of DPRs in human tissues, along with their evaluation in mice and other preclinical models, indicate that the arginine-rich DPRs, poly(GR) and poly(PR), are especially toxic. Our data further suggest that this toxicity stems, at least in part, from the co-condensation and/or co-aggregation of these DPR proteins with proteins that regulate essential cellular functions, such as stress granule biology and nucleocytoplasmic transport. We have also shown that poly(GR) aggregation induces TDP-43 pathology, another hallmark feature of c9ALS/FTD and of the majority of sporadic ALS and FTD cases. Nevertheless, since poly(GR) and poly(PR) interact with more than 200 endogenous proteins, they are likely to adversely influence a host of cellular functions – a line of investigation that merits attention. Also of importance is determining the underlying factors that regulate poly(GR) and poly(PR) condensation and aggregation, and their interactions with other proteins. It is thus notable that our preliminary data show that poly(ADP-ribose) (PAR) promotes poly(GR) and poly(PR) condensation, and enhances their co-condensation or co-aggregation with disease-related proteins in vitro. Moreover, we observed that reducing PAR suppresses poly(GR)- or poly(PR)-mediated neurodegeneration in Drosophila. In light of these exciting findings, we hypothesize that PAR mediates the aggregation and toxicity of arginine-rich DPRs and the proteins to which they bind. Thus, the goal of the proposed project is to determine how PAR does so. To this end, we will identify proteins that interact with poly(GR) or poly(PR) in a PAR-dependent fashion, and investigate the contribution of PAR to arginine-rich DPR aggregation and toxicity using multiple preclinical models and brain tissues from C9orf72 expansion carriers. Overall, by availing the diverse expertise of our team members, we endeavor to elucidate the role of PAR and arginine-rich DPR proteins in c9ALS/FTD pathogenesis, and thus uncover novel therapeutic targets to expedite the development of effective treatments for c9ALS/FTD.