Regulation of Tau Internalization in CNS Cell Culture and Mouse Models of Tauopathy
Jennifer N. Rauch1, John J. Chen2, Alexander W. Sorum3, Gregory M. Miller3, Elmer Guzman1, Linda C. Hsieh-Wilson3, Martin Kampmann2, Kenneth S. Kosik1
1Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
2Institute for Neurodegenerative Diseases, Department of Biochemistry & Biophysics, The California Institute for Quantitative Biomedical Research, Quantitative Biosciences Institute, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
3Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
The misfolding and accumulation of tau protein into intracellular aggregates known as neurofibrillary tangles is a pathological hallmark of neurodegenerative diseases such as Alzheimer's disease. However, while tau propagation is a known marker for disease progression, exactly how tau propagates from one cell to another and what mechanisms govern this spread are still unclear. Using CRISPRi technology we have developed a high throughput screening platform to identify genetic regulators of tau uptake in both H4 neuroglioma culture and iPS-derived neurons. We have identified multiple genes that can regulate tau uptake and have studied their role in cell culture and mouse models of tauopathies. Together, these results suggest novel strategies to halt tau transmission.