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TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease

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Abstract

The rapid confirmation of the initial report by Neumann et al. (Science 314:130–133, 2006) that transactive response (TAR)-DNA-binding protein 43 (TDP-43) is the major disease protein linking frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) with and without motor neuron disease (MND) as well as amyotrophic lateral sclerosis (ALS) implies that TDP-43 proteinopathy underlies major forms of sporadic as well as familial FTLD and ALS. Not only was the identity of the ubiquitinated proteins that accumulate in neurons and glia of these disorders finally resolved, but it also was shown that pathologic TDP-43 was hyperphosphorylated, ubiquitinated and cleaved to generate C-terminal fragments in affected brain and spinal cord of FTLD-U and ALS. This review summarizes the growing evidence that TDP-43 proteinopathy is the common pathologic substrate linking FTLD and ALS, and it considers the implications of these findings for developing better strategies to diagnose and treat these neurodegenerative disorders.

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Acknowledgments

This work was funded by the National Institutes of Health (AG10124, AG17586, and a training grant T32 AG00255 to DMS) and the German Federal Ministry of Education and Research (01G10505). VM-YL is the John H. Ware III Chair of Alzheimer’s Research and JQT is the William Maul Measey-Truman G. Schnabel, Jr, MD Professor of Geriatric Medicine and Gerontology. The authors would like to thank the families of our patients who made this research possible.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    Linda K. Kwong, Deepak M. Sampathu, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Institute on Aging, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    Linda K. Kwong, Deepak M. Sampathu, Virginia M.-Y. Lee & John Q. Trojanowski

  3. Center for Neuropathology and Prion Research, Ludwig-Maximilians University, 81377, Munich, Germany

    Manuela Neumann

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  1. Linda K. Kwong
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  3. Deepak M. Sampathu
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Correspondence to Linda K. Kwong or John Q. Trojanowski.

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Kwong, L.K., Neumann, M., Sampathu, D.M. et al. TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathol 114, 63–70 (2007). https://doi.org/10.1007/s00401-007-0226-5

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