PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) is a progressive brain disorder marked by abnormal protein accumulation and resulting proteotoxicity. This study examines Chaperone-Mediated Autophagy (CMA), particularly substrate translocation into lysosomes, in AD. The study observes: (1) Increased substrate translocation activity into lysosomes, vital for CMA, aligns with AD progression, highlighted by gene upregulation and more efficient substrate delivery. (2) This CMA phase strongly correlates with AD\'s clinical symptoms; more proteotoxicity links to worse dementia, underscoring the need for active degradation. (3) Proteins like GFAP and LAMP2A, when upregulated, almost certainly indicate AD risk, marking this process as a significant AD biomarker. Based on these observations, this study proposes the following hypothesis: As AD progresses, the aggregation of pathogenic proteins increases, the process of substrate entry into lysosomes via CMA becomes active. The genes associated with this process exhibit heightened sensitivity to AD. This conclusion stems from an analysis of over 10,000 genes and 363 patients using two AI methodologies. These methodologies were instrumental in identifying genes highly sensitive to AD and in mapping the molecular networks that respond to the disease, thereby highlighting the significance of this critical phase of CMA.
摘要：
阿尔茨海默病(Alzheimer’sdisease,AD)是一种进行性脑疾病,其特征是异常的蛋白质积累和由此产生的蛋白毒性。这项研究检查了伴侣介导的自噬（CMA），特别是底物易位到溶酶体中，在AD。该研究观察到：（1）增加底物易位到溶酶体的活性，对CMA至关重要,与AD进展一致，突出的是基因上调和更有效的底物递送。（2）CMA阶段与AD的临床症状密切相关；更多的蛋白毒性与更坏的痴呆有关，强调了主动降解的必要性。（3）GFAP和LAMP2A等蛋白质，当上调时，几乎可以肯定表明AD风险，将此过程标记为重要的AD生物标志物。基于这些观察,本研究提出了以下假设：随着AD的进展，致病蛋白的聚集增加，底物通过CMA进入溶酶体的过程变得活跃。与该过程相关的基因对AD表现出增强的敏感性。这一结论来自使用两种AI方法对10,000多个基因和363名患者的分析。这些方法有助于识别对AD高度敏感的基因，并绘制对疾病有反应的分子网络，从而突出了CMA这一关键阶段的重要性。
