Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

Autor: Kenneth S. Kosik, Giovanni Coppola, Daniel H. Geschwind, Yadong Huang, Zhijun Zhang, Anna Karydas, Sandra Almeida, Waltraud Mair, Fen-Biao Gao, M. Helal Uddin Biswas, Helen Fong, Judith A. Steen, M. Catarina Silva, Chialin Cheng, Bruce L. Miller, Stephen J. Haggarty, Sally Temple
Rok vydání: 2016
Předmět:
0301 basic medicine
Aging
Cellular differentiation
Neurodegenerative
Alzheimer's Disease
Biochemistry
0302 clinical medicine
Neural Stem Cells
2.1 Biological and endogenous factors
Protein Isoforms
Aetiology
Induced pluripotent stem cell
Alzheimer's Disease Related Dementias (ADRD)
lcsh:QH301-705.5
Neurons
lcsh:R5-920
Stem Cell Research - Induced Pluripotent Stem Cell - Human
Neurodegeneration
Cell Differentiation
Neural stem cell
3. Good health
Frontotemporal Dementia (FTD)
Frontotemporal Dementia
Neurological
Tauopathy
lcsh:Medicine (General)
Frontotemporal dementia
Physiological
Induced Pluripotent Stem Cells
Clinical Sciences
tau Proteins
Biology
Stress
Article
Cell Line
03 medical and health sciences
Rare Diseases
Downregulation and upregulation
Stress
Physiological
mental disorders
Acquired Cognitive Impairment
Genetics
medicine
Autophagy
Humans
Codon
Protein Processing
Stem Cell Research - Induced Pluripotent Stem Cell
Neurosciences
Post-Translational
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Cell Biology
Stem Cell Research
medicine.disease
Brain Disorders
030104 developmental biology
lcsh:Biology (General)
Amino Acid Substitution
Gene Expression Regulation
Mutation
Dementia
Biochemistry and Cell Biology
Protein Processing
Post-Translational
Neuroscience
030217 neurology & neurosurgery
Biomarkers
Developmental Biology
Zdroj: Stem cell reports, vol 7, iss 3
Silva, MC; Cheng, C; Mair, W; Almeida, S; Fong, H; Biswas, MHU; et al.(2016). Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability. STEM CELL REPORTS, 7(3), 325-340. doi: 10.1016/j.stemcr.2016.08.001. UCLA: Retrieved from: http://www.escholarship.org/uc/item/7n67j0cn
Stem Cell Reports, Vol 7, Iss 3, Pp 325-340 (2016)
Stem Cell Reports
DOI: 10.1016/j.stemcr.2016.08.001.
Popis: Summary 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.
Graphical Abstract Image 1
Highlights • Upregulation of tau and phospho-tau in FTD patient iPSC-derived tau A152T neurons • Upregulation of insoluble tau in A152T neurons • Altered proteostasis stress-inducible pathways in tau A152T neurons • Tau-dependent vulnerability to stress in A152T neurons reverted by tau downregulation
Haggarty and colleagues show in-depth phenotypic characterization of a human iPSC-derived neuronal model of tau-A152T associated with FTD. This study reveals upregulation of phospho-tau and detergent-insoluble oligomeric tau, dysregulation of proteostasis pathways, and consequent increased cell vulnerability to stress, unmasking potential disease biomarkers and therapeutic targets. This study further demonstrates that tau toxicity can be rescued by genetic and pharmacological downregulation of tau.
Databáze: OpenAIRE
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