Investigating the Molecular Mechanisms of Toxicity in Mouse Models of Frontotemporal Dementia

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atmire.contributor.authoremailluke.daly@umassmed.eduen_US
dc.contributor.advisorFen-Biao Gaoen_US
dc.contributor.advisorPaul Greeren_US
dc.contributor.authorDaly, Luke R
dc.contributor.departmentNeurobiologyen_US
dc.contributor.departmentNeurologyen_US
dc.date.accessioned2023-02-24T14:40:27Z
dc.date.available2023-02-24T14:40:27Z
dc.date.issued2022-11-28
dc.description.abstractFrontotemporal Dementia (FTD) is the most common form of presenile dementia and is characterized by impaired cognitive function, behavioral changes, or non-fluent speech aphasia. The most common genetic cause of FTD is a hexanucleotide GGGGCC (G4C2) repeat expansion in the C9orf72 gene (C9orf72-HRE). This thesis outlines a series of in vivo and in vitro experiments undertaken to investigate the molecular mechanisms of toxicity contributing to FTD pathogenesis. In my efforts to characterize the neuroinflammation observed in our Poly(Glycine-Arginine) mouse model of FTD, I found Fkbp5 - a gene our lab previously identified as a modulator of Poly(GR) toxicity - to be significantly downregulated in the cortex of Poly(GR) animals relative to controls. Published RNA sequencing data suggests that Fkbp5 is most highly expressed in microglia of the mammalian brain. However, despite its importance in a variety of neurological disorders, very little is known about the specific role fkbp5 plays in microglia. Data presented in this thesis implicate Fkbp5 as an important modulator of neuroinflammatory signaling and Poly(GR) toxicity. Here, I outline the breeding scheme I devised to generate a novel genetic tool to further untangle the role Fkbp5 may be playing in neuroinflammation and C9orf72 pathogenesis. In additional efforts to investigate the molecular underpinnings of C9orf72 pathology, I contributed to the characterization of a novel AAV9 model of C9orf72-HRE developed by our collaborators at SUNY Upstate Medical University.en_US
dc.description.thesisprogramNeuroscienceen_US
dc.identifier.doi10.13028/g9eq-9757en_US
dc.identifier.orcid0000-0001-8714-0919en_US
dc.identifier.urihttps://hdl.handle.net/20.500.14038/51720
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2022 Dalyen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectFrontotemporal Dementiaen_US
dc.subjectFTDen_US
dc.subjectPoly(GR)en_US
dc.subjectneurodegenerationen_US
dc.titleInvestigating the Molecular Mechanisms of Toxicity in Mouse Models of Frontotemporal Dementiaen_US
dc.typeMaster's Thesisen_US
dspace.entity.typePublication
refterms.dateFOA2023-02-24T14:40:28Z
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