Frontotemporal dementia (FTD) is a spectrum of devastating neurodegenerative diseases characterized by progressive impairment in emotional and social behavior, language and executive function. There are no effective treatments at present, although clinical trials are being planned. Some forms of FTD are inherited in an autosomal dominant manner as a result of a mutation in one of several genes that have been identified. Despite this genetic information, we currently understand very little about the pathways altered in human neurons leading to neurodegeneration. To address this gap in our knowledge, the overall goal of the proposed study is to apply state-of-the-art methods for deriving human induced pluripotent cells (iPSCs) from FTD patients to model aspects of the underlying disease mechanisms and to investigate the step-by-step progression and development of pathophysiology in living human neurons cultured in the laboratory. In this exploratory proposal, we aim to perform a preliminary investigation of individuals who carry one of these genetic mutations. We will obtain skin biopsies and transform the fibroblasts into induced pluripotent cells and then into neurons in culture in order to study abnormalities in cellular metabolic pathways that are specific to each individual's genetic mutation and context. The ultimate goal of this research is to generate neuronal cellular models of FTD to provide a platform for the development of high-content, cell-based assays to be used in chemical and genetic screens for modifiers of tau toxicity, and potential therapeutics that can reverse or prevent disease phenotypes.

Public Health Relevance

Frontotemporal dementia (FTD) is a devastating neurodegenerative disease that causes personality and behavior changes and ultimately results in dementia and death. This project aims to begin to develop new technology to modify skin cells from individuals from families with hereditary FTD so that they grow into brain cells in the lab.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Sutherland, Margaret L
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Massachusetts General Hospital
United States
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Seo, Jinsoo; Kritskiy, Oleg; Watson, L Ashley et al. (2017) Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia. J Neurosci 37:9917-9924
Cheng, Chialin; Fass, Daniel M; Folz-Donahue, Kat et al. (2017) Highly Expandable Human iPS Cell-Derived Neural Progenitor Cells (NPC) and Neurons for Central Nervous System Disease Modeling and High-Throughput Screening. Curr Protoc Hum Genet 92:21.8.1-21.8.21
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Silva, M Catarina; Cheng, Chialin; Mair, Waltraud et al. (2016) Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability. Stem Cell Reports 7:325-340