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Science 6 October 2006:
Vol. 314. no. 5796, pp. 130 - 133
DOI: 10.1126/science.1134108
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Reports

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

Manuela Neumann,1,11* Deepak M. Sampathu,1* Linda K. Kwong,1* Adam C. Truax,1 Matthew C. Micsenyi,1 Thomas T. Chou,2 Jennifer Bruce,1 Theresa Schuck,1 Murray Grossman,3,4 Christopher M. Clark,3,4 Leo F. McCluskey,3 Bruce L. Miller,6 Eliezer Masliah,7 Ian R. Mackenzie,8 Howard Feldman,9 Wolfgang Feiden,10 Hans A. Kretzschmar,11 John Q. Trojanowski,1,4,5 Virginia M.-Y. Lee1,4,5{dagger}

Ubiquitin-positive, tau- and {alpha}-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.

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
2 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
3 Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
4 Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
5 Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
6 Department of Neurology, University of California at San Francisco, CA 94117, USA.
7 Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.
8 Department of Pathology, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
9 Division of Neurology, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
10 Institute for Neuropathology, University of the Saarland, 66421 Homburg, Germany.
11 Center for Neuropathology and Prion Research, Ludwig-Maximilians University, 81377 Munich, Germany.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: vmylee{at}mail.med.upenn.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)