Van Deerlin, Vivianna M

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2015 - 201912020 - 20251
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  • 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.
  • Publication
    Higher Neighborhood Deprivation is Associated with Accelerated Disease Progression in Behavioral-Variant Frontotemporal Degeneration.
    (2025-10-01) Boyle, Rory; Dehghani, Nadia; Emrani, Sheina; Wadhwani, Anil R.; Matyi, Melanie; Cousins, Katheryn A.Q.; Rhodes, Emma; Nelson, Brian; Stites, Shana D.; Xie, Sharon X.; Dratch, Laynie; Van Deerlin, Vivianna M; Snyder, Allison; Irwin, David J.; McMillan, Corey T.; Massimo; Massimo, Lauren M.
    Neighborhood deprivation is associated with shorter survival, cognitive impairment and neurodegeneration in aging and Alzheimer’s disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown. METHODS: We examined associations between tertiles of neighborhood deprivation, using the Area Deprivation Index (ADI), and survival in 311 individuals clinically diagnosed with bvFTD from the Penn FTD Center. In a subset (n=161) with complete baseline data across measures of global cognition, executive function, and language, we examined the association of ADI with longitudinal change. RESULTS: Compared to adults living in the least deprived neighborhoods, those living in the most deprived neighborhoods showed shorter survival after symptom onset and faster decline in global cognition, executive and language functions, independent of genetic risk. DISCUSSION: Living in more deprived neighborhoods was associated with an accelerated disease course in bvFTD, highlighting an important socioeconomic disparity in disease prognosis.