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    Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis (2006)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2006-10-07
    Description: Ubiquitin-positive, tau- and alpha-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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neumann, Manuela -- Sampathu, Deepak M -- Kwong, Linda K -- Truax, Adam C -- Micsenyi, Matthew C -- Chou, Thomas T -- Bruce, Jennifer -- Schuck, Theresa -- Grossman, Murray -- Clark, Christopher M -- McCluskey, Leo F -- Miller, Bruce L -- Masliah, Eliezer -- Mackenzie, Ian R -- Feldman, Howard -- Feiden, Wolfgang -- Kretzschmar, Hans A -- Trojanowski, John Q -- Lee, Virginia M-Y -- AG10124/AG/NIA NIH HHS/ -- AG17586/AG/NIA NIH HHS/ -- T32 AG00255/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2006 Oct 6;314(5796):130-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17023659" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*metabolism/pathology ; Antibodies, Monoclonal ; *Brain Chemistry ; Cerebral Cortex/chemistry/pathology ; DNA-Binding Proteins/*analysis/chemistry/genetics/immunology ; Dementia/genetics/*metabolism/pathology ; Fluorescent Antibody Technique ; Hippocampus/chemistry/pathology ; Humans ; Immunoblotting ; Molecular Sequence Data ; Motor Neurons/chemistry/pathology ; Neurons/chemistry/pathology ; Peptide Fragments/chemistry ; Phosphorylation ; Spinal Cord/*chemistry/pathology ; Ubiquitin/*analysis
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice (2015)
    Oxford University Press
    Details
    Publication Date: 2015-12-01
    Description: Frontotemporal dementia (FTD) causes progressive personality, behavior and/or language disturbances and represents the second most common form of dementia under the age of 65. Over half of all FTD cases are classified pathologically as frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein of 43 kDa (TDP-43) pathology (FTLD-TDP). In FTLD-TDP brains, TDP-43 is phosphorylated, C-terminally cleaved, lost from the nucleus and accumulates in the cytoplasm and processes of neurons and glia. However, the contribution of TDP-43 C-terminal fragments (CTFs) to pathogenesis remains poorly understood. Here, we developed transgenic (Tg) mice with forebrain Camk2a -controlled doxycycline-suppressible expression of a TDP-43 CTF (amino acids 208–414, designated 208 TDP-43 CTF), previously identified in FTLD-TDP brains. In these 208 TDP-43 Tg mice, detergent-insoluble 208 TDP-43 CTF was present in a diffuse punctate pattern in neuronal cytoplasm and dendrites without forming large cytoplasmic inclusions. Remarkably, the hippocampus showed progressive neuron loss and astrogliosis in the dentate gyrus (DG). This was accompanied by phosphorylated TDP-43 in the CA1 subfield, and ubiquitin and mitochondria accumulations in the stratum lacunosum moleculare (SLM) layer, without loss of endogenous nuclear TDP-43. Importantly, 208 TDP-43 CTF and phosphorylated TDP-43 were rapidly cleared when CTF expression was suppressed in aged Tg mice, which ameliorated neuron loss in the DG despite persistence of ubiquitin accumulation in the SLM. Our results demonstrate that Camk2a -directed 208 TDP-43 CTF overexpression is sufficient to cause hippocampal pathology and neurodegeneration in vivo , suggesting an active role for TDP-43 CTFs in the pathogenesis of FTLD-TDP and related TDP-43 proteinopathies.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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