Published online before print June 5, 2008

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(American Journal of Pathology. 2008;173:182-194.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080003

Enrichment of C-Terminal Fragments in TAR DNA-Binding Protein-43 Cytoplasmic Inclusions in Brain but not in Spinal Cord of Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Lionel M. Igaz^*, Linda K. Kwong^*, Yan Xu^*, Adam C. Truax^*, Kunihiro Uryu^*, Manuela Neumann, Christopher M. Clark, Lauren B. Elman, Bruce L. Miller^¶, Murray Grossman, Leo F. McCluskey, John Q. Trojanowski^*|| and Virginia M.-Y. Lee^*||

From the Center for Neurodegenerative Disease Research, Departments of Pathology and Laboratory Medicine^* and Neurology, Alzheimer’s Disease Core Center, Institute on Aging,|| University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany; and the Department of Neurology,^¶ University of California at San Francisco, California

TAR DNA-binding protein (TDP-43) has been recently described as a major pathological protein in both frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. However, little is known about the relative abundance and distribution of different pathological TDP-43 species, which include hyperphosphorylated, ubiquitinated, and N-terminally cleaved TDP-43. Here, we developed novel N-terminal (N-t) and C-terminal (C-t)-specific TDP-43 antibodies and performed biochemical and immunohistochemical studies to analyze cortical, hippocampal, and spinal cord tissue from frontotemporal dementia with ubiquitin-positive inclusions and amyotrophic lateral sclerosis cases. C-t-specific TDP-43 antibodies revealed similar abundance, morphology, and distribution of dystrophic neurites and neuronal cytoplasmic inclusions in cortex and hippocampus compared with previously described pan-TDP-43 antibodies. By contrast, N-t-specific TDP-43 antibodies only detected a small subset of these lesions. Biochemical studies confirmed the presence of C-t TDP-43 fragments but not extreme N-t fragments. Surprisingly, immunohistochemical analysis of inclusions in spinal cord motor neurons in both diseases showed that they are N-t and C-t positive. TDP-43 inclusions in Alzheimer’s disease brains also were examined, and similar enrichment in C-t TDP-43 fragments was observed in cortex and hippocampus. These results show that the composition of the inclusions in brain versus spinal cord tissues differ, with an increased representation of C-t TDP-43 fragments in cortical and hippocampal regions. Therefore, regionally different pathogenic processes may underlie the development of abnormal TDP-43 proteinopathies.

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