Genome-wide CRISPR screen identifies protein pathways modulating tau protein levels in neurons
| Autor: | Fiona Elwood, John Alford, Carsten Russ, Christopher Acker, Audrey Gray, John S. Reece-Hoyes, Carlos G Sanchez, Sarah J. Luchansky, Christian Doherty, Lucas Craig, Gregory McAllister, Steven Paula, Ricardo E. Dolmetsch, Shaojian An, Cheng Song, Alicia Lindeman, Malini Varadarajan, Nadire Cochran, Manuela Polydoro, Ketthsy Capre, Gregory R. Hoffman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CRISPR-Cas9 genome editing
0301 basic medicine Candidate gene QH301-705.5 Tau protein Medicine (miscellaneous) tau Proteins Molecular neuroscience Article General Biochemistry Genetics and Molecular Biology Progressive supranuclear palsy Mice Neuroblastoma 03 medical and health sciences 0302 clinical medicine Ubiquitin CRISPR-Associated Protein 9 Cell Line Tumor mental disorders medicine Animals Humans CRISPR Genetic Testing Biology (General) PI3K/AKT/mTOR pathway Gene Editing Neurons biology TOR Serine-Threonine Kinases Alzheimer's disease medicine.disease Cellular neuroscience Rats Cell biology 030104 developmental biology medicine.anatomical_structure Genes biology.protein Neddylation TSC1 CRISPR-Cas Systems General Agricultural and Biological Sciences Metabolic Networks and Pathways 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021) Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer’s disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau aggregation is unknown, the accumulation of aggregates correlates with disease progression. Here we report a genome-wide CRISPR screen to identify modulators of endogenous tau protein for the first time. Primary screens performed in SH-SY5Y cells, identified positive and negative regulators of tau protein levels. Hit validation of the top 43 candidate genes was performed using Ngn2-induced human cortical excitatory neurons. Using this approach, genes and pathways involved in modulation of endogenous tau levels were identified, including chromatin modifying enzymes, neddylation and ubiquitin pathway members, and components of the mTOR pathway. TSC1, a critical component of the mTOR pathway, was further validated in vivo, demonstrating the relevance of this screening strategy. These findings may have implications for treating neurodegenerative diseases in the future. Using an unbiased genome-wide CRISPR screen approach, Sanchez et al. identified modulators of endogenous tau protein. This study suggests that chromatin modifiers, neddylation, ubiquitination, and the mTOR pathways regulate overall levels of tau protein in neurons, which could help in future identification of therapeutics for neurodegenerative diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|