Autosomal Dominant FTLD Tauopathy Patient-Specific Stem Cell Models

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): 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.