We propose to establish a comprehensive, validated repository of adult human dermal fibroblasts and human induced pluripotent stem cell (hiPSC) lines from frontotemporal dementia (FTD) patients with genetically defined mutations and familial, non-mutation carrying controls. hiPSCs hold tremendous promise for the development of in vitro FTD models for studying disease pathogenesis in relevant human cell types that would otherwise be impossible to obtain, such as human neurons. Using an established, collaborative, multi- institutional approach, we will bank adult human dermal fibroblasts from FTD patients carrying common mutations in the genes currently known to cause FTD: tau (MAPT), C9ORF72, and progranulin (GRN).
In Aim 1, we will recruit both FTD patients with defined genetic mutations and control subjects. Comprehensive and longitudinal clinical evaluations will be linked to each cell line, allowing us to correlate disease characteristics with molecular phenotypes.
In Aim 2, we will reprogram fibroblasts into hiPSCs by non-DNA-integrating technologies with which we have had recent success. In addition, we will further create EGFP reporter lines for monitoring and standardizing differentiation protocols in FTD-relevant cell types such as forebrain neurons. We will also correct selective mutations to create isogenic control lines so that we can precisely differentiate mutation-specific phenotypes from the noise of inter-individual variability.
In Aim 3, we will derive and validate human neurons to model and study FTD pathogenesis in culture and to deliver hiPSC lines with robust phenotypes for FTD research and drug development. Based on our previous research experience in RNA and Tau biology and pathophysiology, we will focus on human neurons with GGGGCC repeat expansions in C9ORF72 and MAPT mutations. All cell lines will be banked at the Coriell Institute and will be accessible to the worldwide FTD research and drug development community. These resources should significantly alter the FTD research landscape by accelerating discovery.
Our goal is to generate and characterize human induced pluripotent stem cell (hiPSC) lines from frontotemporal dementia (FTD) patients carrying defined genetic mutations. We will also establish cell-type specific reporter lines and generate isogenic control lines using zinc finger technologies. We will use these resources as in vitro disease models to directly study FTD pathogenesis and make them available to the worldwide FTD research community. !
|Gao, Fen-Biao; Almeida, Sandra; Lopez-Gonzalez, Rodrigo (2017) Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. EMBO J 36:2931-2950|
|Elahi, Fanny M; Miller, Bruce L (2017) A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 13:457-476|
|Yin, Shanye; Lopez-Gonzalez, Rodrigo; Kunz, Ryan C et al. (2017) Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients. Cell Rep 19:2244-2256|
|Lopez-Gonzalez, Rodrigo; Lu, Yubing; Gendron, Tania F et al. (2016) Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons. Neuron 92:383-391|
|Almeida, Sandra; Gao, Fuying; Coppola, Giovanni et al. (2016) Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients. Neurobiol Aging 42:35-40|
|Kramer, Nicholas J; Carlomagno, Yari; Zhang, Yong-Jie et al. (2016) Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science 353:708-12|
|Biswas, Md Helal U; Almeida, Sandra; Lopez-Gonzalez, Rodrigo et al. (2016) MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations. Stem Cell Reports 7:316-324|
|Yang, Dejun; Abdallah, Abbas; Li, Zhaodong et al. (2015) FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol 130:525-35|
|Freibaum, Brian D; Lu, Yubing; Lopez-Gonzalez, Rodrigo et al. (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525:129-33|
|Tong, Leslie M; Fong, Helen; Huang, Yadong (2015) Stem cell therapy for Alzheimer's disease and related disorders: current status and future perspectives. Exp Mol Med 47:e151|
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