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

恢复蛋白质稳态以解决唐氏综合症的并发病症

• 批准号: 10518555
• 负责人: NIRMALA NIRINJINI NAIDOO
• 金额: $ 185.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518555
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Behavior; Behavioral; Biological; Birth; Brain; Butyrates; Cellular Stress; Chemicals; Child; Chromosome 21; Chromosomes; Cognition; Cognitive; Cognitive deficits; Data; Defect; Deterioration; Down Syndrome; Drowsiness; Early Onset Alzheimer Disease; Elderly; Exhibits; FDA approved; Face; Gene Expression; Genes; Glucose; Glucose Clamp; High Prevalence; Homeostasis; Human Chromosomes; Hyperglycemia; Impaired cognition; Impairment; Individual; Insulin Resistance; Knock-in; Knock-in Mouse; Lead; Leptin resistance; Link; Literature; Longevity; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Middle Insomnia; Modeling; Molecular Chaperones; Mus; Neurons; Obese Mice; Obesity; Orthologous Gene; Pathway interactions; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Phenylbutyrates; Population; Proteins; Publishing; Quality of life; Reporting; Saturated Fatty Acids; Signal Pathway; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Stress; Syndrome; Testing; Therapeutic; Tissues; Urea cycle disorders; aged; biological adaptation to stress; blood glucose regulation; cognitive performance; experience; familial Alzheimer disease; glucose metabolism; high risk; human data; improved; insulin secretion; lipid metabolism; metabolic phenotype; mouse Ts65Dn; mouse model; neuropathology; normal aging; novel therapeutic intervention; overexpression; poor sleep; prevent; protein folding; proteostasis; proteotoxicity; response; restoration; sleep quality; small molecule; therapeutic evaluation

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.

抽象的 唐氏综合症 (DS) 患者的寿命会缩短，并且随着年龄的增长面临严峻的挑战。尽管 主要综合征是由 21 号染色体的额外拷贝引起的，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 经历类似于早发性阿尔茨海默病 (AD) 的认知能力下降。没有统一的 治疗这些同时发生的病症的机制或方法，这可能导致病情急剧恶化 生活质量。已发表的数据和初步数据表明，蛋白质稳态受损和蛋白质的异常激活 蛋白质稳态途径，即未折叠蛋白反应 (UPR)，是 AD 常见的生物机制，被破坏 睡眠和代谢功能障碍。此外，蛋白质折叠应激可能是染色体突变的直接结果。 不平衡以及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 提出患有 DS 的个体容易受到蛋白质折叠应激的影响，并且恢复蛋白质稳态是一个 预防并发疾病的新治疗方法。我们认为减少蛋白质静态 通过化学伴侣 4-苯基丁酸酯 (PBA) 来缓解压力——这是一种小型饱和脂肪酸，已通过 FDA 认证。 批准治疗尿素循环障碍的疗法——反过来会改善睡眠障碍， 新陈代谢和认知。淀粉样前体蛋白 (APP) 是家族性 AD 的关键参与者，是三重蛋白之一 DS 中的基因。 β-淀粉样蛋白 (Aβ) 肽的过度表达和随之而来的过度产生会导致 蛋白质毒性在 DS 人群中 AD 神经病理学的早期发病中发挥着重要作用。我们发现 用 PBA 治疗的 APP 敲入 (APPKI) 小鼠表现出蛋白毒性应激减少并改善认知能力 行为，即使是在认知能力下降后开始治疗。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，多项已发表的研究表明，PBA 恢复肥胖小鼠的代谢功能。因此，该提案的总体假设是减少 FDA 批准的小分子伴侣 PBA 可以减轻蛋白质应激，从而改善睡眠， 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 大约三分之二与人类 21 号染色体直系同源的基因是三体模型，并显示每个 相关表型的分析，以测试 PBA 治疗是否可以挽救这些同时发生的病症。这 该提案建立在支持 PBA 潜力的大量现有文献和新的初步数据的基础上， FDA 批准的一种疗法，用于改善认知能力下降、睡眠障碍和代谢功能障碍。作为 这些病症同时发生在唐氏综合症患者身上，该项目代表了迈向唐氏综合症的关键的第一步 制定统一的治疗方法。