美国斯隆-凯特琳癌症研究所Lorenz Studer和Nathalie Saurat共同合作，近期取得重要工作进展。他们通过全基因组CRISPR筛选鉴定出neddylation是神经元衰老和AD神经退行性病变的调控因子。相关研究成果2024年6月24日在线发表于《细胞—干细胞》杂志上。

据介绍，衰老是阿尔茨海默病（AD）发展的最大风险因素。

研究人员进行了全基因组CRISPR筛选，以确定神经元年龄的调节因子，并表明在人类干细胞模型中，neddylation途径调节细胞年龄和AD神经退行性病变。研究人员证明，阻断neddylation增加了衰老的细胞特征，并导致携带APP^swe/swe突变的神经元中Tau聚集和磷酸化的增加。老化的APP^swe/swe（但不是等基因对照神经元）也表现出生存能力的逐渐降低。在其他等基因AD和帕金森病（PD）模型中，分别包括PSEN^M146V/M146V皮层和LRRK2^{G2019S/G2019S}中脑多巴胺神经元，同样观察到neddylation被抑制后的选择性神经元损失。

总之，这一研究表明，细胞衰老可以揭示晚发性疾病表型，确定调节AD进展的新潜在靶点，并描述了一种将年龄相关表型编程到疾病干细胞模型中的策略。

附：英文原文

Title: Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Author: Nathalie Saurat, Andrew P. Minotti, Maliha T. Rahman, Trisha Sikder, Chao Zhang, Daniela Cornacchia, Johannes Jungverdorben, Gabriele Ciceri, Doron Betel, Lorenz Studer

Issue&Volume: 2024-06-24

Abstract: Aging is the biggest risk factor for the development of Alzheimer’s disease (AD). Here, we performed a whole-genome CRISPR screen to identify regulators of neuronal age and show that the neddylation pathway regulates both cellular age and AD neurodegeneration in a human stem cell model. Specifically, we demonstrate that blocking neddylation increased cellular hallmarks of aging and led to an increase in Tau aggregation and phosphorylation in neurons carrying the APPswe/swe mutation. Aged APPswe/swe but not isogenic control neurons also showed a progressive decrease in viability. Selective neuronal loss upon neddylation inhibition was similarly observed in other isogenic AD and in Parkinson’s disease (PD) models, including PSENM146V/M146V cortical and LRRK2G2019S/G2019S midbrain dopamine neurons, respectively. This study indicates that cellular aging can reveal late-onset disease phenotypes, identifies new potential targets to modulate AD progression, and describes a strategy to program age-associated phenotypes into stem cell models of disease.

DOI: 10.1016/j.stem.2024.06.001

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00210-8