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Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects

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Abstract

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5–10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.

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Acknowledgments

This work was presented at a Round Table Discussion Session at the 8th International Conference on Frontotemporal Dementias, held in Manchester, UK, 6–8 September 2012, and was supported by Springer. GH receives a NHMRC Senior Principal Research Fellowship 630434. EHB is supported by National Institute on Aging grant (P30 AG13854). NJC is supported by grants from the National Institute on Aging of the National Institutes of Health (P50 AG05681 and P01 AG03991), the Hope Center for Neurological Disorders, and the Charles F. and Joanne Knight Alzheimer’s Disease Research Centre. MN is supported by the Swiss National Science Foundation (31003A-132864 and CRSII3-136222), the German Federal Ministry of Education and Research (01GI1005B), and the Hans and Ilse Breuer Foundation. IRM is funded by the Canadian Institutes of Health Research Grants (179009 and 74580), and the Pacific Alzheimer’s Research Foundation Center Grant (C06-01). DMAM is supported by grants from the Wellcome Trust and Medical Research Council, and the Manchester Brain Bank receives funding from Alzheimers Research UK and Alzheimers Society through the Brains for Dementia Research Initiative.

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Authors and Affiliations

  1. Neuroscience Research Australia, University of New South Wales, Sydney, Australia

    Glenda Halliday

  2. Alzheimer Disease Center, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Eileen H. Bigio

  3. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA

    Nigel J. Cairns

  4. Department of Neuropathology, German Center for Neurodegenerative Diseases Tuebingen, University of Tuebingen, Tuebingen, Germany

    Manuela Neumann

  5. Department of Pathology, University of British Columbia, Vancouver, Canada

    Ian R. A. Mackenzie

  6. Institute of Brain, Behaviour and Mental Health, School of Community Based Medicine, University of Manchester, Manchester, UK

    David M. A. Mann

  7. Salford Royal Hospital, University of Manchester, Stott Lane, Salford, M6 8HD, UK

    David M. A. Mann

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  1. Glenda Halliday
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Correspondence to David M. A. Mann.

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Halliday, G., Bigio, E.H., Cairns, N.J. et al. Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects. Acta Neuropathol 124, 373–382 (2012). https://doi.org/10.1007/s00401-012-1030-4

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