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Abstract
Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recently, a p.A152T tau variant was identified as a risk factor for FTD, Alzheimer's disease, and synucleinopathies. Here we used induced pluripotent stem cells (iPSC) from a patient carrying this p.A152T variant to create a robust, functional cellular assay system for probing pathophysiological tau accumulation and phosphorylation. Using stably transduced iPSC-derived neural progenitor cells engineered to enable inducible expression of the pro-neural transcription factor Neurogenin 2 (Ngn2), we generated disease-relevant, cortical-like glutamatergic neurons in a scalable, high-throughput screening compatible format. Utilizing automated confocal microscopy, and an advanced image-processing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specific effects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to affect tau phosphorylation. These results demonstrate the potential for using patient iPSC-derived ex vivo models of tauopathy as genetically accurate, disease-relevant systems to probe tau biochemistry and support the discovery of novel therapeutics for tauopathies.
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1 Massachusetts General Hospital and Harvard Medical School, Department of Neurology, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
2 University of North Carolina School of Medicine, Department of Pharmacology, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208); Indiana University School of Medicine, Department of Pediatrics, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
3 University of North Carolina School of Medicine, Department of Pharmacology, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208)
4 University of Florida, Department of Biochemistry & Molecular Biology, Center for NeuroGenetics, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091)
5 University of Florida, Department of Molecular Genetics & Microbiology, Center for NeuroGenetics, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091)
6 Massachusetts General Hospital and Harvard Medical School, Center for Genomic Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
7 Massachusetts Institute of Technology, Picower Institute for Learning and Memory, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786)
8 University of California, Department of Neurology, Memory and Aging Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
9 Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, USA (GRID:grid.443945.b) (ISNI:0000 0004 0566 7998)
10 Neuroscience Research Institute, University of California, Department of Molecular, Cellular and Developmental Biology, Santa Barbara, USA (GRID:grid.133342.4) (ISNI:0000 0004 1936 9676)
11 Massachusetts General Hospital and Harvard Medical School, Department of Neurology, MGH Frontotemporal Disorders Unit, Charlestown, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
12 Massachusetts General Hospital and Harvard Medical School, Department of Neurology, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Massachusetts General Hospital and Harvard Medical School, Department of Neurology, MGH Frontotemporal Disorders Unit, Charlestown, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)