Trojanowski, John Q

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2008 - 200912010 - 20151
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  • Publication
    Exploring Human/Animal Intersections: Converging Lines of Evidence in Comparative Models of Aging
    (2008-01-01) Trojanowski, John Q; Aguirre, Gustavo D; Jedrziewski, Kathryn; Johnson, F. Brad; Hess, Rebecka S; Cancro, Michael P; Sleeper, Margaret M; Pignolo, Robert; Lee, Virginia Man-Yee; Hendricks, Joan C; Pack, Allan I; Davies, Peter F; Michel, Kathryn E; Teff, Karen L; Lawler, Dennis F
    At a symposium convened on March 8, 2007 by the Institute on Aging at the University of Pennsylvania, researchers from the University’s Schools of Medicine and Veterinary Medicine explored the convergence of aging research emerging from the two schools. Studies in human patients, animal models, and companion animals have revealed different but complementary aspects of the aging process, ranging from fundamental biologic aspects of aging to the treatment of age-related diseases, both experimentally and in clinical practice. Participants concluded that neither animal nor human research alone will provide answers to most questions about the aging process. Instead, an optimal translational research model supports a bidirectional flow of information from animal models to clinical research.
  • Publication
    Transcriptomic Changes Due to Cytoplasmic TDP-43 Expression Revel Dysregulation of Histone Transcripts and Nuclear Chromatin
    (2015-01-01) Amlie-Wolf, Alexandre; Ryvkin, Paul; Tong, Rui; Suh, EunRan; Xu, Yan; Van Deerlin, Vivianna M; Gregory, Brian D; Trojanowski, John Q; Lee, Virginia Man-Yee; Wang, Li-San; Lee, Edward B; Dragomir, Isabelle; Kwong, Linda K
    AR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display dramatic changes in gene expression as measured by microarray, suggesting that cytoplasmic TDP-43 may be associated with a toxic gain-of-function. Here, we analyze new RNA-sequencing data from the ΔNLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice to investigate further the dysregulation of gene expression in the ΔNLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3’ untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.