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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,1Matthew C. Micsenyi,1Thomas T. Chou,2Jennifer Bruce,1Theresa Schuck,1Murray Grossman,3,4Christopher M. Clark,3,4Leo F. McCluskey,3Bruce L. Miller,6Eliezer Masliah,7Ian R. Mackenzie,8Howard Feldman,9Wolfgang Feiden,10Hans A. Kretzschmar,11John Q. Trojanowski,1,4,5Virginia M.-Y. Lee1,4,5
Ubiquitin-positive, tau- and -synucleinnegative inclusionsare hallmarks of frontotemporal lobar degeneration with ubiquitin-positiveinclusions and amyotrophic lateral sclerosis. Although the identityof the ubiquitinated protein specific to either disorder wasunknown, we showed that TDP-43 is the major disease proteinin both disorders. Pathologic TDP-43 was hyper-phosphorylated,ubiquitinated, and cleaved to generate C-terminal fragmentsand was recovered only from affected central nervous systemregions, including hippocampus, neocortex, and spinal cord.TDP-43 represents the common pathologic substrate linking theseneurodegenerative 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.
To whom correspondence should be addressed. E-mail: vmylee{at}mail.med.upenn.edu
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