Restoration of proteostasis to address co-occurring conditions in Down Syndrome

摘要 唐氏综合症(DS)患者的寿命缩短，并随着年龄的增长面临严峻的挑战。而当 原发综合征是由21号染色体的额外拷贝引起的，并且从出生起就存在，患有DS的人 患睡眠和代谢紊乱的风险要高得多，超过三分之二的人 经历类似早发性阿尔茨海默病(AD)的认知衰退。没有统一的 治疗这些并存疾病的机制或方法，这些并存疾病可能导致 生活质量。已发表的和初步的数据表明，蛋白平衡受损和异常激活的蛋白 蛋白平衡途径，即未折叠蛋白反应(UPR)，是AD常见的一种生物学机制，被破坏 睡眠和代谢功能障碍。此外，蛋白质折叠压力可能是染色体的直接结果。 不平衡和来自人类和小鼠的数据支持DS中异常UPR诱导的概念。因此，我们 提出DS患者容易受到蛋白质折叠应激的影响，恢复蛋白质平衡是一种 预防共病的新的治疗方法。我们假设减少蛋白质组分 通过化学伴侣4-苯基丁酸酯(PBA)-一种FDA的小型饱和脂肪酸-应激- 被批准用于治疗尿素循环障碍的疗法--反过来将改善睡眠障碍， 新陈代谢和认知。淀粉样前体蛋白(APP)是家族性阿尔茨海默病(AD)的三重基因之一，在家族性AD中起关键作用。 DS中的基因。淀粉样β蛋白(Aβ)多肽的过度表达和随之而来的过度生产导致 蛋白毒性在DS人群中AD神经病理的早期发病中起重要作用。我们发现了 用PBA治疗的APPKI小鼠表现出减少蛋白毒性应激并改善认知能力 行为，即使在认知衰退开始后开始治疗也是如此。我们的数据还表明，PBA 改善APPKI和正常衰老小鼠的睡眠质量。此外，几项已发表的研究表明，PBA 恢复肥胖小鼠的代谢功能。因此，这一提议的全球假设是减少 FDA批准的小分子伴侣PBA将改善睡眠， DS小鼠模型中的代谢和行为缺陷。我们将使用经过验证的DS Ts65Dn鼠标 约三分之二与人类21号染色体同源的基因的三体模型，并显示每个 以测试PBA治疗是否拯救了这些共生疾病中的每一种。这 该提案建立在大量现有文献和支持PBA潜力的新初步数据的基础上， FDA批准的一种治疗方法，用于改善认知衰退、睡眠障碍和代谢功能障碍。AS 这些情况在唐氏综合症患者中同时发生，该项目代表着迈向 开发一种统一的治疗方法。

ABSTRACT Individuals with Down syndrome (DS) have shortened lifespan and face severe challenges as they age. While the primary syndrome is caused by an extra copy of chromosome 21, and is present from birth, those with DS are at a much higher risk of developing sleep and metabolic disorders and more than two thirds of individuals experience cognitive decline that resembles early-onset Alzheimer's disease (AD). There is no unified mechanism or approach to treating these co-occurring conditions, which can lead to a drastic deterioration in quality of life. Published and preliminary data indicate that impaired proteostasis and aberrant activation of the proteostasis pathway, the unfolded protein response (UPR), is a biological mechanism common to AD, disrupted sleep and metabolic dysfunction. Moreover, protein folding stress can be a direct consequence of chromosome imbalance and data from humans and mice support the concept of aberrant UPR induction in DS. Thus, we propose that individuals with DS are susceptible to protein folding stress and that restoring proteostasis is a novel therapeutic approach to prevent co-occurring conditions. We posit that reducing proteostatic stress via chemical chaperone 4-phenyl butyrate (PBA) – a small saturated fatty acid that is an FDA- approved therapy for treatment of urea cycle disorders – will in turn ameliorate disturbances in sleep, metabolism, and cognition. Amyloid precursor protein (APP), a key player in familial AD, is one of the triplicated genes in DS. Overexpression and the consequent overproduction of amyloid beta (Aβ)-peptide leads to proteotoxicity that is instrumental in the early onset of AD neuropathology in the DS population. We have found that APP knockin (APPKI) mice treated with PBA display reduced proteotoxic stress and improved cognitive behavior, even when treatment was initiated after the onset of cognitive decline. Our data also indicate that PBA improves sleep quality in APPKI and normally aging mice. Moreover, several published studies indicate that PBA restores metabolic function in obese mice. Therefore, the global hypothesis of this proposal is that reduction of proteostatic stress with the FDA-approved small molecule chaperone PBA will ameliorate sleep, metabolic and behavioral deficits in a mouse model of DS. We will use the validated DS Ts65Dn mouse model that is trisomic for about two-thirds of the genes orthologous to human chromosome 21 and displays each of the relevant phenotypes to test whether PBA treatment rescues each of these co-occurring conditions. This proposal builds on a strong body of existing literature and new preliminary data supporting the potential of PBA, an FDA-approved therapy, for improving cognitive decline, sleep disturbances, and metabolic dysfunction. As these conditions co-occur in individuals with Down syndrome, this project represents a crucial first step towards developing a unified therapeutic approach.