The effect of juevnille protective programs on protein aggregation during aging

描述(申请人提供)：许多迟发性神经退行性疾病，如亨廷顿病(HD)、阿尔茨海默病(AD)和肌萎缩侧索硬化症(ALS)，都是由蛋白质的错误折叠和聚集引起的。这些疾病的最终风险因素是衰老。此外，在这些疾病中，容易聚集的蛋白质会影响神经元，随着疾病的发展，神经元越来越失去功能。患有这些疾病的人会屈从于与他们相关的有害症状，如痴呆症和运动功能丧失，最终死亡。目前，这些疾病还没有治愈的方法，只有很少的治疗方法可以减少潜在症状。最终，更具创新性的治疗方法的产生对治疗将是最重要的，并有望治愈，了解与防止蛋白质聚集有关的细胞和遗传途径将有所帮助。在神经退行性疾病中，易于聚集的蛋白质在出生时就会表达，尽管疾病的症状直到晚年才出现。此外，具有相同基因突变蛋白的个体在发病年龄上也存在很大的差异。这表明，青少年项目的存在可以在以后的生活中保护一些抵抗者。研究人员一直在研究已知的保护途径，以避免或延缓蛋白质稳态的破坏，从而延缓或减少蛋白质聚集的毒性效应。这些方法已经找到了许多改善蛋白质平衡的方法，尽管往往存在延迟发育和繁殖的风险。因此，这项研究的目标是确定在青少年阶段起作用的途径 防止蛋白质聚集，并与生命后期的正常发育、生长和细胞信号相兼容。这将通过解决以下问题来实现：通过耐应激的Dauer阶段的短暂过渡是否可以防止蛋白质聚集，并防止与以后生命中的蛋白质毒性相关的表型？最终，我们的目标是确定青少年在衰老过程中被激活时具有保护作用的机制。秀丽线虫有一种生理保护程序(达尔滞育)，众所周知，这种程序可以抵抗压力，防止衰老。上述问题将通过在生命早期瞬时激活Dauer程序，随后允许正常发育，并观察这些处理对蛋白质聚集和衰老期间毒性的影响来解决。

DESCRIPTION (provided by applicant): Many late-onset neurodegenerative diseases, such as Huntington's disease (HD), Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS), are caused by the misfolding and aggregation of proteins. The ultimate risk factor for these diseases is aging. Also, in these diseases aggregate-prone proteins affect neurons, which increasingly lose function as the disease advances with age. Individuals stricken with these diseases succumb to the detrimental symptoms associated with them, such as dementia and loss of motor function and ultimately death. Currently, there are no cures for these diseases, and only few treatments to reduce the underlying symptoms are available. Ultimately, the production of more innovative therapeutic approaches will be most important for treatment, and hopefully cure, and understanding of the cellular and genetic pathways involved with protection against protein aggregation will help. In neurodegenerative diseases the aggregation-prone proteins are expressed at birth, although symptoms of disease are not present until later in life. Also, there exists great variability in age of onset among individuals who have the same genetically mutated protein. This suggests the presence of juvenile programs that can protect some resistant individuals later in life. Researchers have been studying known protective pathways that avoid or delay the failure of protein homeostasis (proteostasis) and thus delay or deduce toxic effects of protein aggregation. These approaches have found many ways to improve proteostasis, although often at the risk for delaying development and reproduction. Therefore, the goal of this research is to identify the pathways that act during juvenile stages to protect against protein aggregation and are compatible with normal development, growth, and cellular signaling later in life. This will be accomplished by addressing the following questions: does transient passage through stress-resistant dauer stage protect against protein aggregation, and from phenotypes associated with proteotoxicity later in life? And ultimately, our goal is to identify the mechanisms that are protective during aging when activated in juveniles. Caenorhabditis elegans has a physiological protective program (dauer diapause) that is known to be stress-resistant and protected from aging. The above questions will be addressed by transiently activating dauer program early in life, subsequently allowing for normal development, and observing the effects of these treatments on protein aggregation and toxicity during aging.