Frontotemporal dementia (FTD), a devastating, rapidly progressive neurodegenerative disease, accounts for 15-20% of all dementia cases and particularly common in patients under 65 years of age. FTD patients suffer progressive neurodegeneration in the frontal lobes and other brain regions, resulting in behavioral changes, and memory and motor neuron deficits. Compared with other age-dependent neurodegenerative diseases, the molecular, cellular, and genetic bases of FTD are poorly understood, although there is increasing recognition of pathological overlap with other neurodegenerative diseases. Genetic causes are estimated to account for ~40% of FTD, and since 1998, dominant mutations in four causative genes have been identified. These include mutations of tau, valosin-containing protein (VCP), CHMP2B, and progranulin. The identification of these genes allows for the generation of sorely needed animal models of FTD. The overall goal of this proposal it to generate murine models for FTD, focusing on progranulin and VCP. Murine models will enable detailed study of the pathogenesis, testing of genetic interactions between contributing mechanisms, and testing of emerging therapies.
Aim 1 is to generate mouse models for FTD caused by progranulin deficiency. Specifically, we will generate mice lacking progranulin in the whole body and, with Cre-LoxP methodology, in neurons and microglia. Additionally, we will generate mice that harbor a disease- specific nonsense mutation (corresponding to the human mutation R493X), which will provide a model for testing therapies that target non-sense mutations.
Aim 2 is to generate transgenic mice expressing human VCP with an FTD mutation (R155H) in neurons. We will also test whether a genetic interaction exists between VCP mutations and Pgrn mutations by crossing the different models. The phenotypes of each of these potential disease models will be extensively analyzed, many aspects with the assistance of expert local collaborators.These.mouse models will enable us to complement on-going cell-based studies of disease pathogenesis with in vivo testing of emerging hypotheses. The mice will also be deposited in public repositories, making them generally available to the research community.

Public Health Relevance

(Seeinstructions): Dementias due to progressive loss of brain function are huge health problems confronting our population. Frontotemporal dementia (FTD), a rapidly progressive and devastating disease, is less well known than Alzheimer's disease but is emerging as a relatively common cause of dementia. Currently, there are no cures and there are no proven animal models. We propose to generate mouse models of FTD, both to study how the disease occurs and to provide a means to test new therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of California San Francisco
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Mansoor, Yael; Jastrzab, Laura; Dutt, Shubir et al. (2015) Memory profiles in pathology or biomarker confirmed Alzheimer disease and frontotemporal dementia. Alzheimer Dis Assoc Disord 29:135-40
Wagshal, Dana; Sankaranarayanan, Sethu; Guss, Valerie et al. (2015) Divergent CSF ? alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 86:244-50
Greene, Meredith; Steinman, Michael A; McNicholl, Ian R et al. (2014) Polypharmacy, drug-drug interactions, and potentially inappropriate medications in older adults with human immunodeficiency virus infection. J Am Geriatr Soc 62:447-53
Rosen, Howard J; Alcantar, Oscar; Zakrzewski, Jessica et al. (2014) Metacognition in the behavioral variant of frontotemporal dementia and Alzheimer's disease. Neuropsychology 28:436-47
Beecham, Gary W; Hamilton, Kara; Naj, Adam C et al. (2014) Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. PLoS Genet 10:e1004606
Minikel, Eric Vallabh; Zerr, Inga; Collins, Steven J et al. (2014) Ascertainment bias causes false signal of anticipation in genetic prion disease. Am J Hum Genet 95:371-82
Laforce Jr, Robert; Tosun, Duygu; Ghosh, Pia et al. (2014) Parallel ICA of FDG-PET and PiB-PET in three conditions with underlying Alzheimer's pathology. Neuroimage Clin 4:508-16
El Magraoui, Fouzi; Eisenacher, Martin; Schrötter, Andreas et al. (2014) Developing new methods to answer old and new questions in neurodegenerative diseases: 21(st) Workshop of the HUPO Brain Proteome Project (HBPP) 23-24 January 2014, Honolulu, Hawaii. Proteomics 14:1308-10
James, Bryan D; Leurgans, Sue E; Hebert, Liesi E et al. (2014) Contribution of Alzheimer disease to mortality in the United States. Neurology 82:1045-50
Walsh, Christine M; Wilkins, Sarah; Bettcher, Brianne Magouirk et al. (2014) Memory consolidation in aging and MCI after 1 week. Neuropsychology 28:273-80

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