Abstract
TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of the pathological inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy, also called FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and motor neuron disease (MND). TDP-43 is predominantly expressed in the nucleus and regulates gene expression and splicing. In FTLD with TDP-43 proteinopathy, neuronal inclusions present variably as cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), and intranuclear inclusions (NIIs), leading to a fourfold neuropathological classification correlating with genotype. There have been few fine structural studies of these inclusions. Thus, we undertook an immunoelectron microscopic study of FTLD with TDP-43 proteinopathy, including sporadic and familial cases with progranulin (GRN) mutation. TDP-43-immunoreactive inclusions comprised two components: granular and filamentous. Filament widths, expressed as mean (range) were: NCI, 9 nm (4–16 nm); DN, 10 nm (5–16 nm); NII, 18 nm (9–50 nm). Morphologically distinct inclusion components may reflect the process of TDP-43 aggregation and interaction with other proteins: determining these latter may contribute towards understanding the heterogeneous pathogenesis of FTLD with TDP-43 proteinopathy.
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Acknowledgments
We thank the families of patients whose generosity made this research possible. We acknowledge the staff of the Alzheimer’s Disease Research Center Neuropathology Laboratory, Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, USA and Max Allin, University of Sussex, for technical assistance. Support for this work was provided by grants from the Wellcome Trust, UK, (GR066166AIA) to JRT and NJC, and the National Institute on Aging of the National Institutes of Health (P50 AG05681 and P01 AG03991) to NJC.
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Supported by grants to JRT and NJC from the Wellcome Trust (GR066166AIA), and National Institute on Aging of the National Institutes of Health (P50 AG05681 and P01 AG03991) to NJC.
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Thorpe, J.R., Tang, H., Atherton, J. et al. Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. J Neural Transm 115, 1661–1671 (2008). https://doi.org/10.1007/s00702-008-0137-1
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DOI: https://doi.org/10.1007/s00702-008-0137-1