Stephen J. Haggarty, PhD
Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

Stem Cell Reports. 2016 Sep 13;7(3):325-40. doi: 10.1016/j.stemcr.2016.08.001. Epub 2016 Sep 1.

Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanismof neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant.We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.


Vanessa Wheeler

Dr. Wheeler received her Ph.D. in Molecular Genetics from the Imperial College of Science, Technology and Medicine in London and carried out postdoctoral training at Massachusetts General Hospital. Her research […]

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James Walker

Dr. Jim Walker received his Ph.D. in Biochemistry from the University of Cambridge and carried out post-doctoral training at Massachusetts General Hospital. His research focuses on understanding the genetics and […]

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Michael Talkowski

Dr. Talkowski received a Ph.D. in human genetics and performed his postdoctoral training in neurodevelopmental genomics. The Talkowski laboratory is interested in understanding the consequence of genomic variation on human […]

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Kathryn J. Swoboda

Dr. Swoboda received her medical degree at The Northwestern Feinberg School of Medicine. She completed her neurology residency at the Harvard Longwood Neurology Program at the Brigham and Women’s Hospital, […]

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David Sweetser

Dr. Sweetser received his B.S. in Biological Science with Honors from Stanford University in 1982, his M.D./Ph.D. at Washington University in St. Louis, followed by a  Pediatric Residency at St. […]

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Alexander Soukas

Dr. Soukas received his Sc.B. in Biomedical Engineering from Brown University, M.D. (Alpha Omega Alpha) from Cornell University Medical College, and Ph.D. in molecular genetics from the Rockefeller University. He […]

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Jordan W. Smoller

Dr. Smoller is Professor of Psychiatry at HMS, and Professor in Epidemiology at the Harvard T.H. Chan School of Public Health. At MGH, he is the Trustees Endowed Chair in Psychiatric […]

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Susan A. Slaugenhaupt

My research focuses on two neurological disorders, familial dysautonomia (FD) and mucolipidosis type IV (MLIV), as well as the common cardiac disorder mitral valve prolapse (MVP).   Our work is focused […]

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Jeremiah Scharf

Dr. Scharf is a behavioral neurologist and human geneticist whose lab uses genetic and clinical research tools to identify the underlying cause(s) and pathogenesis of Tourette Syndrome (TS) and related […]

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