AbstractFrontotemporal dementia (FTD) is a clinically, genetically and pathologically heterogeneous disorder characterised by a change in language, behaviour and personality, which can also be accompanied by the signs of motor neuron disease (MND). Further, it is considered to be the second most common form of presenile dementia. Pathologically, it is characterised by atrophy of the frontal and anterior temporal lobes. In 2006, TDP-43 was identified as the major component of the ubiquitinated neuronal inclusions found in both frontotemporal lobar degeneration (FTLD) and MND. However, the role of TDP-43 in the neurodegenerative process of FTLD and MND is not yet fully understood. Identifying the TDP-43 protein network could assist in understanding TDP-43’s pathological mechanism in neurodegeneration.
In this study, I screened for candidate TDP-43-binding proteins in the brain and spinal cord tissue of FTLD and MND cases using immunohistochemistry. Striking inclusions were detected with hnRNP-E2 in the brain of 16 out of 30 FTLD-TDP cases which do not carry the C9orf72 mutation. The hnRNP-E2 pathology is significantly related to the TDP-43 pathological subtypes A and C. Furthermore, hnRNP-E2 inclusions colocalised with 84.5% of TDP-43 inclusions and with 67% of ubiquitin inclusions that were also seen in the brain tissue of the FTLD-TDP cases found to exhibit hnRNP-E2 pathology. hnRNP-E2 inclusions were not detected in any of the other neurodegenerative diseases examined in this study, which suggests the close relation of hnRNPE2 to the pathology of TDP-43.
In order to explore the mechanistic connection between TDP-43 and hnRNP-E2 as well as the possible role of this interaction in TDP-43 pathogenesis, cell biology techniques were utilised to manipulate the levels of TDP-43 and hnRNP-E2 expression in the HEK293T cell line. The knockdown of hnRNP-E2 caused a significant reduction in the TDP-43 levels; however, the interaction was not confirmed. Yet, the hnRNP-E2 interacted with the TDP-43 in the stress granules of HeLa cells under combined osmotic and oxidative stress. At this point, it remains unclear how and why hnRNP-E2 interacted with TDP-43 in a subset of FTLD-TDP cases. However, the results presented here demonstrate that the role of hnRNP-E2 in TDP-43 proteinopathy warrants further investigation.
|Date of Award
|Tibor Hortobagyi (Supervisor), Jean-Marc Gallo (Supervisor), Claire Troakes (Supervisor) & Christopher Shaw (Supervisor)