Published:
[Erscheinungsort nicht ermittelbar]: University of New South Wales. Clinical School - St Vincent's Hospital, 2010
Language:
English
Origination:
University thesis:
Dissertation, University of New South Wales. Clinical School - St Vincent's Hospital, 2010
Footnote:
Description:
Frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia after Alzheimer's disease (AD). It is a clinically, neuropathologically and genetically heterogeneous syndrome. With the exception of mutations in the MAPT, GRN, VCP and CHMP2B genes, the aetiology of FTLD remains largely unknown and to date no effective treatments exist. In two families with FTLD and motor neuron disease (MND), immunohistochemical analysis revealed two quite distinct neuropathologies. To identify the genes involved in the pathogenesis of FTLD-MND, linkage analysis was carried out. Family Aus-12 failed to show significant linkage to any known genetic locus but showed suggestive linkage to chromosome 15. These findings together with the unusual pathology of a combined tauopathy and TDP-43 proteinopathy suggest that this family represents a novel genetic form of FTLD-MND. A genome-wide linkage analysis of family Aus-14, which shows a concomitant TDP-43 and FUS pathology, revealed a significant association to chromosome 9p where most FTLD-MND families show linkage. A positional candidate gene analysis led to the identification of a single nucleotide change (c.672*51G>T) in the 3' untranslated region of the sigma-1 receptor gene (SIGMAR1). Its non-polymorphic nature was verified using multiple control cohorts. A SIGMAR1 mutation screen conducted in Australian FTLD probands and two Polish presenile dementia cohorts identified two more presumptive mutations (c.672*26C>T and c.672*47G>A). Functional studies revealed that the three mutations lead to significant dysregulation of SIGMAR1 expression. Subsequent investigations revealed that consistent with the identified cytoplasmic TDP-43 and FUS inclusions in c.672*51G>T mutation carriers, overexpression of sigma-1 receptor (sigma-1R) resulted in significant shunting of TDP-43 and FUS from the nucleus to the cytoplasm. Antisense knock down of sigma-1R expression resulted in lowered cytoplasmic TDP-43 and FUS levels suggesting a common underlying pathogenic mechanism. Furthermore, treatment of cells with sigma-1R ligands significantly altered TDP-43 subcellular localisation. These results provide a potential therapeutic strategy for the treatment of FTLD and MND, diseases with underlying TDP-43 and/or FUS pathology, through the use of known sigma-1R ligands.