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.

@article{citeulike:2878395, abstract = {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.}, address = {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.}, author = {Igaz, Lionel M M. and Kwong, Linda K K. and Xu, Yan and Truax, Adam C C. and Uryu, Kunihiro and Neumann, Manuela and Clark, Christopher M M. and Elman, Lauren B B. and Miller, Bruce L L. and Grossman, Murray and McCluskey, Leo F F. and Trojanowski, John Q Q. and Lee, Virginia M-Y M. }, citeulike-article-id = {2878395}, doi = {http://dx.doi.org/10.2353/ajpath.2008.080003}, issn = {1525-2191}, journal = {The American journal of pathology}, keywords = {als, frontotemporal\_dementia, tdp-43}, month = {June}, posted-at = {2008-06-10 01:56:30}, priority = {4}, title = {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.}, url = {http://dx.doi.org/10.2353/ajpath.2008.080003}, year = {2008} }

TY - JOUR ID - citeulike:2878395 L3 - citeulike-article-id:2878395 N2 - 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. JF - The American journal of pathology SN - 1525-2191 AD - 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. TI - 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. KW - als KW - frontotemporal_dementia KW - tdp-43 AU - Igaz, Lionel M AU - Kwong, Linda K AU - Xu, Yan AU - Truax, Adam C AU - Uryu, Kunihiro AU - Neumann, Manuela AU - Clark, Christopher M AU - Elman, Lauren B AU - Miller, Bruce L AU - Grossman, Murray AU - McCluskey, Leo F AU - Trojanowski, John Q AU - Lee, Virginia M-Y PY - 2008/06/05/ UR - http://dx.doi.org/10.2353/ajpath.2008.080003 ER -