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Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases

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Abstract

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to α-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.

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Acknowledgments

The authors would like to thank T. Schuck and J. Robinson for their expert technical assistance and our collaborators within and beyond the Center for Neurodegenerative Disease Research (CNDR) who contributed to the studies reviewed here from CNDR. Further, they thank their patients and families who made this research possible. This work was funded by the National Institutes of Health (AG10124, AG17586).

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  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 3600 Spruce Street, Philadelphia, PA, 19104-4283, USA

    Felix Geser, Maria Martinez-Lage, Linda K. Kwong, Virginia M.-Y. Lee & John Q. Trojanowski

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  1. Felix Geser
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  2. Maria Martinez-Lage
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Correspondence to Felix Geser.

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Geser, F., Martinez-Lage, M., Kwong, L.K. et al. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol 256, 1205–1214 (2009). https://doi.org/10.1007/s00415-009-5069-7

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