Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

American Association for the Advancement of Science (AAAS) - Tập 314 Số 5796 - Trang 130-133 - 2006
Manuela Neumann1,2,3,4,5, Deepak M. Sampathu1,2,3,4,5, Linda K. Kwong1,2,3,4,5, Adam C. Truax1,2,3,4,5, Matthew C. Micsenyi1,2,3,4,5, Thomas T. Chou1,2,3,4,5, Jennifer Bruce1,2,3,4,5, Theresa Schuck1,2,3,4,5, Murray Grossman1,2,3,4,5, Christopher M. Clark1,2,3,4,5, Leo McCluskey1,2,3,4,5, Bruce L. Miller1,2,3,4,5, Eliezer Masliah1,2,3,4,5, Ian R. Mackenzie1,2,3,4,5, Howard Feldman1,2,3,4,5, W. Feiden1,2,3,4,5, Hans A. Kretzschmar1,2,3,4,5, John Q. Trojanowski1,2,3,5, Virginia M.‐Y. Lee1,2,3,5
1Alzheimer’s Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
2Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 USA
3Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
4Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
5Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

Tóm tắt

Ubiquitin-positive, tau- and α-synuclein–negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

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Tài liệu tham khảo

10.1038/nm1113

10.1002/ana.20203

10.1007/s00401-004-0900-9

J. K. Johnson et al., Arch. Neurol.62, 925 (2005).

10.1007/s00401-005-1079-4

10.1002/ana.20873

10.1001/archneur.58.11.1803

10.1017/S1355617702814357

10.1212/WNL.51.6.1546

10.1212/WNL.59.7.1077

10.1038/nature05016

10.1038/nature05017

10.1002/ana.410430617

10.1038/31508

10.1038/sj.mp.4001198

10.1093/brain/awh724

10.1212/WNL.50.6.1546

D. M. Sampathu et al. Am. J. Pathol. in press.

Materials and methods are available as supporting material on Science Online.

10.1128/jvi.69.6.3584-3596.1995

10.1093/emboj/20.7.1774

10.1016/S0888-7543(03)00214-3

10.1097/01.jnen.0000174335.27708.0a

10.1016/j.jmb.2005.02.038

10.1093/nar/gki897

10.1086/420978

10.1073/pnas.212483099

Z. He, A. Bateman, J. Mol. Med.1, 600 (2003).

We thank the Penn Proteomics Core Facility for the LC-MS/MS and M. Forman for critical comments on the manuscript. This work was funded by NIH (grants AG10124 AG17586 and T32 AG00255) and German Brain Bank “Brain-Net” (grant 01GI0299).

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American Association for the Advancement of Science (AAAS)

Tập 314 Số 5796

130-133

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