Nathalie Saurat, Andrew P. Minotti, Maliha T. Rahman, Trisha Sikder, Chao Zhang, Daniela Cornacchia, Johannes Jungverdorben, Gabriele Ciceri, Doron Betel, Lorenz Studer
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引用次数: 0
摘要
衰老是阿尔茨海默病(AD)发病的最大风险因素。在这里,我们进行了一次全基因组CRISPR筛选,以确定神经元年龄的调控因子,并在人类干细胞模型中表明,neddylation通路调控着细胞年龄和阿兹海默症神经退行性变。具体来说,我们证明阻断neddylation会增加细胞的衰老特征,并导致携带APPswe/swe突变的神经元中Tau聚集和磷酸化的增加。衰老的APPswe/swe神经元而非同源对照神经元的存活率也逐渐下降。在其他同源 AD 和帕金森病(PD)模型中,包括 PSENM146V/M146V 皮层神经元和 LRRK2G2019S/G2019S 中脑多巴胺神经元中,也同样观察到了抑制 neddylation 后神经元选择性丧失的现象。这项研究表明,细胞衰老可以揭示晚发疾病的表型,确定了调节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。
Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration
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.
期刊介绍:
Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.