Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration Journal Article
| Authors: | Saurat, N.; Minotti, A. P.; Rahman, M. T.; Sikder, T.; Zhang, C.; Cornacchia, D.; Jungverdorben, J.; Ciceri, G.; Betel, D.; Studer, L. |
| Article Title: | Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration |
| 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. © 2024 The Author(s) |
| Keywords: | aging; senescence; alzheimer's disease; cortical neurons; neddylation; dopamine neurons; parkinson's disease; disease modeling; human pluripotent stem cells; proteostasis |
| Journal Title: | Cell Stem Cell |
| Volume: | 31 |
| Issue: | 8 |
| ISSN: | 1934-5909 |
| Publisher: | Cell Press |
| Date Published: | 2024-08-01 |
| Start Page: | 1162 |
| End Page: | 1174.e8 |
| Language: | English |
| DOI: | 10.1016/j.stem.2024.06.001 |
| PUBMED: | 38917806 |
| PROVIDER: | scopus |
| PMCID: | PMC11405001 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK authors are Nathalie Saurat and Lorenz Studer -- Source: Scopus |
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