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）的个体寿命缩短，并且随着年龄的增长而面临严重的挑战。尽管 主要综合征是由21号染色体的额外副本引起的，并且从出生开始，患有DS 患睡眠和代谢疾病的风险要高得多，三分之二以上的人 经历类似于早期发作的阿尔茨海默氏病（AD）的认知下降。没有统一 处理这些同时发生条件的机制或方法，这可能导致严重的确定 生活质量。已发布和初步数据，表明蛋白质量受损和异常激活 蛋白质途径是展开的蛋白质反应（UPR），是一种常见的生物学机制，破坏了 睡眠和代谢功能障碍。此外，蛋白质折叠应力可能是染色体的直接结果 人类和小鼠的失衡和数据支持DS中异常UPR诱导的概念。那，我们 提议DS患者容易受到蛋白质折叠应力的影响，并且恢复蛋白质是一种 防止同时发生条件的新型热方法。我们肯定会减少蛋白抑制作用 通过化学伴侣4-苯基丁酸酯（PBA）的压力 - 一种小饱和脂肪酸，是FDA- 批准治疗尿素周期疾病的疗法 - 反过来又可以改善睡眠的疾病， 代谢和认知。家族广告中的关键参与者淀粉样蛋白前体蛋白（APP）是一式三份 ds中的基因。过表达以及淀粉样β（Aβ）肽的过量产生导致 蛋白质毒性在DS种群的AD神经病理学的早期发作中发挥了作用。我们找到了 用PBA治疗的那个应用敲击（AppKi）小鼠显示蛋白毒性应激减少并改善了认知能力 行为，即使在认知下降开始后开始治疗。我们的数据还表明PBA 改善Appki和通常老化小鼠的睡眠质量。此外，一些已发表的研究表明PBA 恢复肥胖小鼠的代谢功能。因此，该提议的全球假设是减少 具有FDA批准的小分子伴侣PBA的蛋白质应力将改善睡眠， 代谢和行为在DS的小鼠模型中定义。我们将使用经过验证的DS TS65DN鼠标 模型是三分之二的三分之二的基因与人类染色体的基因的模型 相关表型测试PBA治疗是否反应这些同时发生的条件。这 建议建立在现有文献和新的初步数据的基础上，这些数据支持PBA的潜力， 通过FDA批准的疗法，可改善认知能力下降，睡眠障碍和代谢功能障碍。作为 这些条件在唐氏综合症患者中共发生，该项目代表了迈向的至关重要的第一步 开发统一的治疗方法。