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

Manuela Neumann; Deepak M. Sampathu; Linda K. Kwong; Adam C. Truax; Matthew C. Micsenyi; Thomas T. Chou; Jennifer Bruce; Theresa Schuck; Murray Grossman; Christopher M. Clark; Leo F. McCluskey; Bruce L. Miller; Eliezer Masliah; Ian R. Mackenzie; Howard Feldman; Wolfgang Feiden; Hans A. Kretzschmar; John Q. Trojanowski; Virginia M.-Y. Lee

doi:10.1126/science.1134108

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

Manuela Neumann1,11,*,
Deepak M. Sampathu1,*,
Linda K. Kwong1,*,
Adam C. Truax1,
Matthew C. Micsenyi1,
Thomas T. Chou2,
Jennifer Bruce1,
Theresa Schuck1,
Murray Grossman3,4,
Christopher M. Clark3,4,
Leo F. McCluskey3,
Bruce L. Miller6,
Eliezer Masliah7,
Ian R. Mackenzie8,
Howard Feldman9,
Wolfgang Feiden10,
Hans A. Kretzschmar11,
John Q. Trojanowski1,4,5,
Virginia M.-Y. Lee1,4,5,†

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.

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

↵* These authors contributed equally to this work.

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Science 06 Oct 2006:
Vol. 314, Issue 5796, pp. 130-133
DOI: 10.1126/science.1134108

Manuela Neumann

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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

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Deepak M. Sampathu

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Linda K. Kwong

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Adam C. Truax

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Matthew C. Micsenyi

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Thomas T. Chou

2 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Jennifer Bruce

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Theresa Schuck

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Murray Grossman

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.

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Christopher M. Clark

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.

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Leo F. McCluskey

3 Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Bruce L. Miller

6 Department of Neurology, University of California at San Francisco, CA 94117, USA.

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Eliezer Masliah

7 Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.

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Ian R. Mackenzie

8 Department of Pathology, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

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Howard Feldman

9 Division of Neurology, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

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Wolfgang Feiden

10 Institute for Neuropathology, University of the Saarland, 66421 Homburg, Germany.

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Hans A. Kretzschmar

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

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John Q. Trojanowski

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, 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.

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Virginia M.-Y. Lee

1 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, 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.

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For correspondence: vmylee@mail.med.upenn.edu

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Abstract

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

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