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Characterisation of Frontotemporal Lobar Degeneration with Motor Neuron Disease

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Characterisation of Frontotemporal Lobar Degeneration with Motor Neuron Disease Characterisation of Frontotemporal Lobar Degeneration with Motor Neuron Disease Agnes Anna Luty A thesis submitted for the degree of Doctor of Philosophy in the Faculty of Medicine, University of New South Wales and Neuroscience Research Australia 2010 ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date ……………………………………………….............. ii COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International. I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date ……………………………………………........................... AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………………........................... Date ……………………………………………........................... iii December 17, 2010 Supervisor Certification This is to certify that as primary supervisor I have confirmed that all co-authors of the following published or submitted papers agree to Agnes Luty submitting these papers as part of her doctoral thesis. Furthermore, with the exception of Dr Clement Loy, none of the co-authors has, or intends to submit, any of the work covered by these papers as part of a separate thesis. Dr Loy intends to submit the work as part of his PhD thesis. Dr Loy's work involved the recruitment and clinical assessment of the families examined in this study, whereas Agnes Luty contributions to these two papers included the practical details of experimental design, the majority of the laboratory experimental work and data analysis and the drafting of the manuscripts. With regard to the contents of the submitted manuscript, I certify that in my professional opinion the work is complete and is of a standard and significance that it is highly likely to be accepted for publication in the journal Brain. Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Short CL, Field CD, Panegyres PK, Hecker J, Blair IP, Halliday GM, Schofield PR. Corticobasal pathology in a large FTD-MND family with suggestive linkage to chromosome 15q21-q23 (Undergoing revisions following submission to Brain). Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR. Pedigree with frontotemporal lobar degeneration-motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol. 2008; 8: 32. Luty AA, Kwok JB, Dobson-Stone C, Loy CT, Coupland KG, Karlström H, Sobow T, Tchorzewska J, Maruszak A, Barcikowska M, Panegyres PK, Zekanowski C, Brooks WS, Williams KL, Blair IP, Mather KA, Sachdev PS, Halliday GM, Schofield PR. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann Neurol. 2010; 68: 639-49. Yours Sincerely, Professor Peter R Schofield iv Declaration of contributions to publications As first author, my contribution to the three papers included in this thesis involved the practical experimental design, undertaking the majority of experimental work and data analyses and writing of the first draft of the manuscripts. The overall concept design for each study as well as practical supervision and advice was provided by my PhD supervisors PR Schofield and JB Kwok. The pedigrees, disease and control cohorts were collected and assessed by EM Thompson, WS Brooks, CD Field, PK Panegyres, CT Loy, CL Short and J Hecker. GA Nicholson provided the MND cohort; J Tchorzewska, A Maruszak, T Sobow, M Barcikowska, C Zekanowski provided the Polish cohorts; and KM Mather and PS Sachdev provided the Memory and Ageing Study (MAS) cohort. P Blumbergs and GM Halliday provided expertise in diagnosis and interpretation of the neuropathological findings. For the manuscript submitted to Brain, I conducted the majority of the experimental work and linkage analysis, with clinical and neuropathological inputs as detailed above. For the paper published in BMC Neurology, I conducted the majority of the experimental work and linkage analysis, with clinical and neuropathological contributions detailed above. Sequencing of MND genes was carried out by KL Williams and IP Blair. For the paper published in Annals of Neurology, I carried out the mutation screen of candidate genes and identified the SIGMAR1 mutation. I screened the Sydney Older Person Study cohort, familial presenile dementia cohort and the Polish presenile dementia cohorts for SIGMAR1 mutations. I conducted the TDP-43 and sigma-1 receptor immunohistochemistry and double immunofluorescence. I did the quantification of sigma-1 receptor and TDP-43 transcript levels. Primer design and construct generation was carried out with advice and assistance from H Karlström. Cell culture and brain tissue analyses were conducted by C Dobson-Stone. KG Coupland conducted the v microRNA experiment. KL Williams and IP Blair sequenced SIMGAR1 in MND and control cohorts. Clinical and neuropathological contributions are as detailed above. vi ACKNOWLEDGEMENTS Foremost, I would like to thank my supervisors Peter Schofield and John Kwok for the opportunity to work on this incredible project. I can’t thank them enough for their constant support, encouragement and patience especially over the last few years. A sincere thank you to Glenda Halliday for her invaluable advice and assistance with the project. I would also like to extend a special thank you to Helena Karlström for all her guidance and support in and out of the lab during my stay in Sweden. Many thanks to Bill Brooks for his assistance with the clinical aspect of the project. A huge thank you to all the members of the lab, especially Marianne Hallupp who has helped me out with countless experiments and has always been a great friend. Ian, Kerrie, Clement and Carol, thank you for always providing a helping hand when needed most. Dom, Lottie, Erica, Rushie, Jen, Connie and Paris - thank you for your support, friendship, many fond memories and the laughs that we’ve shared. Most importantly, many thanks to my family, Mum, Dad and Annette for being the inspiration that I needed to get through an otherwise arduous journey. Mr and Mrs Dengate, thank you for being my extended family and for all your support. Finally, I would like to thank Chris who has been incredibly patient and has stood by me every step of the way. I could not have done this without him. vii Abstract 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.
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