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Role of transportin-1 in the pathogenesis of FTLD-FUS: a pathological, biochemical and cellular study

Brelstaff, JH; (2014) Role of transportin-1 in the pathogenesis of FTLD-FUS: a pathological, biochemical and cellular study. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common form of pre-senile dementia. Recent discoveries have identified the proteins present in the pathological ubiquitinated inclusions of previously undifferentiated subtypes of FTLD. Fused in Sarcoma (FUS) is the primary pathological marker of a subtype now called FTLD-FUS. This normally nuclear protein is seen within the cytoplasmic and intranuclear aggregates of FTLD-FUS. FUS, together with Ewing’s Sarcoma (EWS) and TATA box binding associated factor 68kDa (TAF15), forms the FET family. These related proteins are predominately nuclear owing to the action of the nuclear importin Transportin1 (TRN1). Investigations by other authors have implicated TRN1 in the cytoplasmic aggregation of ALS-associated mutant FUS. Since ALS and FTLD represent different ends of a disease spectrum, the role of TRN1 in the pathology and biochemistry of FTLD-FUS was investigated. Extensive TRN1, TAF15 and EWS cytoplasmic and intranuclear inclusions were seen throughout the frontal cortex, hippocampus and entorhinal cortex, medulla, XIIth cranial nerve nucleus and spinal cord. Double-label immunofluorescence revealed TRN1 and FUS pathology co-localised. Immunoblotting of solubility fractions demonstrated that highly insoluble, likely highly aggregated TRN1 is present in FTLD-FUS, and not in healthy controls. Stress granules are transient cytoplasmic foci consisting of stalled translation initiation complexes and associated proteins produced by the cell in response to various stressors. Cellular investigations revealed that the same antibodies used to detect TRN1 pathology in FTLD-FUS labelled cytoplasmic stress granules induced after oxidative or osmotic stress. The re-localisation of wild type endogenous FET proteins was investigated under various pharmacological agents as well as TRN1 knockdown and overexpression. Evidence is presented that the pathology of FTLD-FUS is more complex than previously thought. Cellular studies investigate the implication of stress granules in aggregate formation and find that there is evidence to support oxidative stress in protein re-localisation and aggregation.

Type: Thesis (Doctoral)
Title: Role of transportin-1 in the pathogenesis of FTLD-FUS: a pathological, biochemical and cellular study
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1421170
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