TTR and C9ORF72 in ALS and related disorders

 描述（由申请人提供）：我们试图确定甲状腺素运载蛋白（TTR）在肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）中的作用，该作用与9号染色体开放阅读框72（C9 ORF 72）中的重复扩增有关，以及TTR是否可以作为C9 ORF 72相关疾病急需的生物标志物。尽管新出现的证据表明C9 ORF 72表达的丧失、RNA灶的形成和二肽重复蛋白的产生有助于C9 ORF 72相关疾病，但关于这些致命性神经退行性疾病的致病机制仍有很多未知之处。更重要的是，在携带扩展点的患者中描述的大量临床变异性 其他基因的参与加速或减轻疾病的进展。为了阐明哪些基因可能驱动ALS和FTD表型的致病异质性，并鉴定潜在的生物标志物，我们首先进行了全基因组脑表达分析，重点是C9 ORF 72扩增载体。我们令人兴奋的初步数据显示，与疾病对照组（即没有C9 ORF 72重复扩增的ALS和FTD患者）和没有神经系统疾病的对照组相比，扩增携带者中TTR和多同源框（HOX）基因的小脑上调。参与发育过程的基因的鉴定揭示了影响C9 ORF 72相关疾病发生、呈现和/或进展的潜在代偿机制。此外，我们表明，TTR蛋白水平在血浆中也增加了扩展载体，从而反映了小脑TTR表达的增加。鉴于TTR具有神经保护作用，参与神经退行性疾病，并且在血浆和脑脊液（CSF）中均可检测到，我们假设TTR可作为C9 ORF 72相关疾病的生物标志物。 为了解决已经描述用于诊断目的、作为预后指标或监测药物作用的C9 ORF 72相关疾病的经验证的生物标志物的缺乏，我们的目标是表征TTR在C9 ORF 72扩增携带者中的上调并确定TTR是否可以是合适的生物标志物。我们对C9 ORF 72相关疾病中TTR的全面评估将包括研究症状性和症状前C9 ORF 72扩增携带者、疾病对照和无神经系统疾病对照的独特队列中的TTR蛋白水平（血浆和CSF），这将允许在组、疾病亚组（例如FTD、FTD/ALS和ALS）和随时间推移进行比较（目标1）。此外，我们将描述TTR在一系列神经解剖区域中的上调，评估组织病理学背景，并检查存在哪些翻译后修饰（目的2）。总之，这些研究将使我们能够确定TTR是否是C9 ORF 72相关疾病的合适生物标志物，这可能有助于鉴定整个ALS和FTD谱的生物标志物谱，并为这些毁灭性神经退行性疾病提供新的治疗方法。

 DESCRIPTION (provided by applicant): We seek to determine the role of transthyretin (TTR) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72), and whether TTR may serve as a much needed biomarker for C9ORF72-related diseases. Although emerging evidence suggests loss of C9ORF72 expression, the formation of RNA foci, and the generation of dipeptide-repeat proteins contribute to C9ORF72-related diseases, much remains unknown about the pathogenic mechanisms underlying these fatal neurodegenerative diseases. More important, the substantial clinical variability described in patients carrying the expansion points to the involvement of other genes functioning to accelerate or mitigate disease progression. To elucidate which genes may be driving the pathogenic heterogeneity in ALS and FTD phenotypes and to identify potential biomarkers, we first performed a genome-wide brain expression analysis focusing on C9ORF72 expansion carriers. Our exciting preliminary data show a cerebellar up-regulation of TTR and multiple homeobox (HOX) genes, in expansion carriers as compared to disease controls (i.e. ALS and FTD patients without C9ORF72 repeat expansions) and to controls without neurological diseases. The identification of genes involved in developmental processes sheds light on potential compensatory mechanisms influencing the occurrence, presentation and/or progression of C9ORF72- related diseases. Moreover, we show that TTR protein levels in plasma are also increased in expansion carriers, thus reflecting the increase in cerebellar TTR expression. Given that TTR has neuroprotective effects, is involved in neurodegenerative diseases, and is detectable in both plasma and cerebrospinal fluid (CSF), we hypothesize that TTR may serve as a biomarker for C9ORF72-related diseases. To address the lack of validated biomarkers for C9ORF72-related diseases that have been described for diagnostic purposes, as prognostic indicators, or to monitor drug effects, we aim to characterize the up- regulation of TTR in C9ORF72 expansion carriers and to determine whether TTR could be a suitable biomarker. Our thorough assessment of TTR in C9ORF72-related diseases will include investigating TTR protein levels (plasma and CSF) in a unique cohort of symptomatic and presymptomatic C9ORF72 expansion carriers, disease controls, and controls without neurological diseases, which will allow comparisons among groups, disease subgroups (e.g. FTD, FTD/ALS, and ALS), and over time (Aim 1). Moreover, we will characterize the up-regulation of TTR in a range of neuroanatomical regions, evaluate the histopathological context, and examine which post-translational modifications are present (Aim 2). Taken together, these studies will enable us to determine whether TTR is a suitable biomarker for C9ORF72-related diseases, which may aid the identification of biomarker profiles for the entire ALS and FTD spectrum, and point towards novel therapies for these devastating neurodegenerative diseases.