Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability.
Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of 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.
Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
M Catarina
MC
Silva
Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Chialin
C
Cheng
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Waltraud
W
Mair
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Sandra
S
Almeida
Departments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA.
Helen
H
Fong
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
M Helal U
MHU
Biswas
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Zhijun
Z
Zhang
Departments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA.
Yadong
Y
Huang
Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, NY 12144, USA.
Sally
S
Temple
Departments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USA.
Giovanni
G
Coppola
Departments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USA.
Daniel H
DH
Geschwind
Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA.
Anna
A
Karydas
Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA.
Bruce L
BL
Miller
Department of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA.
Kenneth S
KS
Kosik
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Fen-Biao
FB
Gao
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Judith A
JA
Steen
Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: shaggarty@mgh.harvard.edu.
Stephen J
SJ
Haggarty
D019943:Amino Acid Substitution; D001343:Autophagy / Q000235:genetics; D015415:Biomarkers; D002454:Cell Differentiation; D002460:Cell Line; D003062:Codon; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D013312:Stress, Physiological; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; D003062:Codon; D020033:Protein Isoforms; D016875:tau Proteins