PT  - JOURNAL ARTICLE
AU  - Polanco, Juan Carlos
AU  - Akimov, Yevhen
AU  - Fernandes, Avinash
AU  - Briner, Adam
AU  - Hand, Gabriel Rhys
AU  - van Roijen, Marloes
AU  - Balistreri, Giuseppe
AU  - Götz, Jürgen
TI  - CRISPRi screening reveals regulators of tau pathology shared between exosomal and vesicle-free tau
AID  - 10.26508/lsa.202201689
DP  - 2023 Jan 01
TA  - Life Science Alliance
PG  - e202201689
VI  - 6
IP  - 1
4099  - http://www.life-science-alliance.org/content/6/1/e202201689.short
4100  - http://www.life-science-alliance.org/content/6/1/e202201689.full
SO  - Life Sci. Alliance2023 Jan 01; 6
AB  - The aggregation of the microtubule-associated protein tau is a defining feature of Alzheimer’s disease and other tauopathies. Tau pathology is believed to be driven by free tau aggregates and tau carried within exosome-like extracellular vesicles, both of which propagate trans-synaptically and induce tau pathology in recipient neurons by a corrupting process of seeding. Here, we performed a genome-wide CRISPRi screen in tau biosensor cells and identified cellular regulators shared by both mechanisms of tau seeding. We identified ANKLE2, BANF1, NUSAP1, EIF1AD, and VPS18 as the top validated regulators that restrict tau aggregation initiated by both exosomal and vesicle-free tau seeds. None of our validated hits affected the uptake of either form of tau seeds, supporting the notion that they operate through a cell-autonomous mechanism downstream of the seed uptake. Lastly, validation studies with human brain tissue also revealed that several of the identified protein hits are down-regulated in the brains of Alzheimer’s patients, suggesting that their decreased activity may be required for the emergence or progression of tau pathology in the human brain.