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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 -synuclein–negative 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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A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology.
J. B. Leverenz, C. E. Yu, T. J. Montine, E. Steinbart, L. M. Bekris, C. Zabetian, L. K. Kwong, V. M-Y. Lee, G. D. Schellenberg, and T. D. Bird (2007)
Brain
130, 1360-1374
|Abstract »|Full Text »|PDF »
Rates of cerebral atrophy differ in different degenerative pathologies.
J. L. Whitwell, C. R. Jack Jr, J. E. Parisi, D. S. Knopman, B. F. Boeve, R. C. Petersen, T. J. Ferman, D. W. Dickson, and K. A. Josephs (2007)
Brain
130, 1148-1158
|Abstract »|Full Text »|PDF »
March 13 Highlight and Commentary: Weft and warp: Molecular pathology and clinical genetics knit a fabric of neurodegeneration.
Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation.
S. Spina, J. R. Murrell, E. D. Huey, E. M. Wassermann, P. Pietrini, M. A. Baraibar, A. G. Barbeito, J. C. Troncoso, R. Vidal, B. Ghetti, et al. (2007)
Neurology
68, 820-827
|Abstract »|Full Text »|PDF »
A 34-year-old man with progressive behavioral and language disturbance.
B. L. Miller, K. A. Josephs Jr, J. E. Parisi, and B. M. Keegan (2007)
Neurology
68, 68-74
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Linking Selective Vulnerability to Cell Death Mechanisms in Parkinson's Disease.
D. W. Dickson (2007)
Am. J. Pathol.
170, 16-19
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-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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