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P1‐028: Gamma—secretase modulators do not show a potency shift in high expressing model systems
Author(s) -
Bronk Brian,
Tate Barbara,
Loureiro Robyn,
Austin Wesley,
Creaser Steffen,
Fuller Nathan,
Hubbs Jed
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.308
Subject(s) - potency , gamma secretase , chemistry , transgene , amyloid precursor protein secretase , genetically modified mouse , cleavage (geology) , in vitro , microbiology and biotechnology , amyloid precursor protein , pharmacology , biochemistry , biology , alzheimer's disease , gene , medicine , disease , paleontology , fracture (geology)
ubiquitin-positive inclusion bodies. Besides aggregation of TDP-43, ubiquitination, hyperphosphorylation, fragmentation and loss of nuclear localization was observed in diseases. However, it remains to be clarified whether TDP-43 aggregates are toxic or not, and how abnormality of TDP-43 mediates neuronal degeneration. Methods: We show here that the cells with TDP-43 inclusions suppressed cell-growth, using BrdU up-take analysis. And morphological relationship between TDP-43 inclusion and several transcription factors were detected in immunocytochemical analysis. Results: We report here that cell-growth is strongly suppressed in the cells with TDP-43 inclusions compared to the cells without inclusions. In these cells, RNA polymerase II and several transcription factors are co-localized with TDP-43 aggregates. Furthermore, accumulation of RNA polymerase II with phosphorylated TDP-43 inclusions was detected in FTLD brains. These results suggested that abnormal TDP-43 inclusions cause growth arrest in SH-SY5Y cells by recruiting general transcription factors and leading to toxicity or cellular dysfunction. Conclusions: In TDP-43 proteinopathy, transcriptional dysregulation may also contribute to neuronal degeneration.