Sanchez Bautista, Javier; (2024) The role of mitochondria in progranulinrelated frontotemporal dementia. Doctoral thesis (Ph.D), UCL (University College London).

Text JavierBautista_PhDThesis_Submission.pdf - Accepted Version Access restricted to UCL open access staff until 1 June 2025. Download (12MB)

Abstract

Mutations in the progranulin (GRN) gene are a major cause of frontotemporal dementia (FTD), resulting in haploinsufficiency of the soluble protein progranulin (PGRN). While mitochondrial dysfunction is considered a key mediator in the pathogenesis of several neurological disorders, the impact of PGRN haploinsufficiency on mitochondrial activity remains largely underexplored. The overall aim of this thesis was to characterise the role of mitochondria in GRN-related FTD. Initially, I conducted a comprehensive characterisation of mitochondria in GRN knockdown immortalised cell lines, fibroblasts from patients with GRN pathogenic mutations and iPSCderived neurons and astrocytes. This involved biochemical, molecular and genetic approaches. Subsequently, I investigated the role of mitochondria in human post-mortem brains diagnosed with frontotemporal lobar degeneration (FTLD), comparing FTLD-GRN cases with sporadic FTLD-TDP cases and controls. Finally, I optimised histopathology techniques and developed semi-automatic quantitative techniques to identify and measure neuropathological changes in FTLD-GRN cases. The experimental work in PGRN-deficient in vitro and human post-mortem brains revealed mitochondrial bioenergetic deficits, decreased mitochondrial mass, and mtDNA maintenance defects. These findings collectively establish the presence of mitochondrial dysfunction in GRN-related FTD. The data strongly implicate mitochondria as organelles affected by PGRN deficiency, suggesting that mitochondrial dysfunction is involved in GRNrelated FTD pathogenesis. Consequently, mitochondria emerge as potential therapeutic targets for treating FTLD-GRN patients.

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