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Endogenous progesterone levels and frontotemporal dementia: Modulation of TDP-43 and Tau levels in vitro and treatment of A315T TARDBP mouse model
Endogenous progesterone levels and frontotemporal dementia: Modulation of TDP-43 and Tau levels in vitro and treatment of A315T TARDBP mouse model
dc.contributor.author | Dang, Theresa NT | en_US |
dc.contributor.author | Dobson-Stone, Carol | en_US |
dc.contributor.author | Kim, Woojin S | en_US |
dc.contributor.author | Hallup, Marianne | en_US |
dc.contributor.author | Bartley, Lauren | en_US |
dc.contributor.author | Piguet, Olivier | en_US |
dc.contributor.author | Halliday, Glenda | en_US |
dc.contributor.author | Hodges, John R | en_US |
dc.contributor.author | Double, Kay L | en_US |
dc.contributor.author | Schofield, Peter R | en_US |
dc.contributor.author | Crouch, Peter J | en_US |
dc.contributor.author | Kwok, John BJ | en_US |
dc.contributor.author | Glaros, Elias N | en_US |
dc.date.accessioned | 2021-11-25T12:29:12Z | |
dc.date.available | 2021-11-25T12:29:12Z | |
dc.date.issued | 2013 | en_US |
dc.description.abstract | Clinical variants of Frontotemporal dementia (FTD) include semantic dementia (SD) and progressive nonfluent aphasia (PNFA). Together with the closely related disorders FTD with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), they constitute a major cause of young onset dementia. The steroid hormone progesterone (PROG) has an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall (Exp(B) = 2.6, adjusted p = 0.019). In our subgroup analysis, low PROG levels were significantly associated with FTD-MND (N = 12, Exp(B) = 5.0, adjusted p = 0.022) and CBS (N = 10, Exp(B) = 5.9, adjusted p = 0.017), but not with the other subgroups. PROG levels of > 195 pg/mL were significantly correlated with lower disease severity (Frontotemporal dementia rating Scale) for CBS patients (N = 6, standardized β = -0.92, adjusted p = 0.0002). In the human neuroblastoma SK-N-MC cell line, exogenous progesterone (9300 to 93,000 pg/mL) had a significant effect on overall tau and nuclear TDP-43 levels, reducing total tau levels by approximately 1.5 fold (p < 0.05) and increasing nuclear TDP-43 by 1.7 to 2.0 fold (p < 0.05). Finally, elevation of serum PROG to approximately 6000 pg/mL in an Ala315Thr TARDBP mutant mouse model significantly reduced the rate of loss of locomotor control (adjusted p = 0.033) in PROG treated compared with placebo mice. The PROG treatment did not significantly increase survival of the mice, and may be due to the limitation of the transgenic mouse to accurately model TDP-43 mediated neurodegeneration. Nonetheless, our clinical, cellular and animal data provide strong evidence that PROG may be a valid therapy for specific related disorders of FTD. | en_US |
dc.identifier.issn | 1754-8403 | en_US |
dc.identifier.uri | http://hdl.handle.net/1959.4/53600 | |
dc.language | English | |
dc.language.iso | EN | en_US |
dc.rights | CC BY-NC-ND 3.0 | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/au/ | en_US |
dc.source | Legacy MARC | en_US |
dc.subject.other | corticobasal syndrome | en_US |
dc.subject.other | frontotemporal dementia | en_US |
dc.subject.other | motor neuron disease | en_US |
dc.subject.other | progressive non-fluent aphasia | en_US |
dc.subject.other | TAR DNA binding protein -43 | en_US |
dc.subject.other | progressive supranuclear palsy | en_US |
dc.subject.other | tau | en_US |
dc.subject.other | progesterone | en_US |
dc.title | Endogenous progesterone levels and frontotemporal dementia: Modulation of TDP-43 and Tau levels in vitro and treatment of A315T TARDBP mouse model | en_US |
dc.type | Journal Article | en |
dcterms.accessRights | open access | |
dspace.entity.type | Publication | en_US |
unsw.accessRights.uri | https://purl.org/coar/access_right/c_abf2 | |
unsw.identifier.doiPublisher | http://dx.doi.org/10.1242/dmm.011460 | en_US |
unsw.relation.FunderRefNo | 630434 | en_US |
unsw.relation.faculty | Medicine & Health | |
unsw.relation.fundingScheme | NHMRC Project | en_US |
unsw.relation.ispartofissue | 5 | en_US |
unsw.relation.ispartofjournal | Disease Models and Mechanisms | en_US |
unsw.relation.ispartofpagefrompageto | 1198-1204 | en_US |
unsw.relation.ispartofvolume | 6 | en_US |
unsw.relation.originalPublicationAffiliation | Dang, Theresa NT, 1. Department of Pathology, The University of Melbourne, VIC, Australia | en_US |
unsw.relation.originalPublicationAffiliation | Dobson-Stone, Carol, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Kim, Woojin S, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Hallup, Marianne, NeuRA | en_US |
unsw.relation.originalPublicationAffiliation | Bartley, Lauren, NeuRA | en_US |
unsw.relation.originalPublicationAffiliation | Piguet, Olivier, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Halliday, Glenda, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Hodges, John R, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Double, Kay L, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Schofield, Peter R, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Crouch, Peter J, 1. Department of Pathology, The University of Melbourne, VIC, Australia, 5. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia | en_US |
unsw.relation.originalPublicationAffiliation | Kwok, John BJ, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Glaros, Elias N, Centre for Vascular Research, Faculty of Medicine, UNSW | en_US |
unsw.relation.school | Neuroscience Research Australia | * |
unsw.relation.school | School of Medical Sciences | * |
unsw.subject.fieldofresearchcode | 110903 Central Nervous System | en_US |
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