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Transcriptional programs mediating neuronal toxicity and altered glial-neuronal signaling in a Drosophila knock-in tauopathy model.
Bukhari, Hassan; Nithianandam, Vanitha; Battaglia, Rachel A; Cicalo, Anthony; Sarkar, Souvarish; Comjean, Aram; Hu, Yanhui; Leventhal, Matthew J; Dong, Xianjun; Feany, Mel B.
Afiliación
  • Bukhari H; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
  • Nithianandam V; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815.
  • Battaglia RA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
  • Cicalo A; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815.
  • Sarkar S; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
  • Comjean A; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815.
  • Hu Y; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815.
  • Leventhal MJ; Genomics and Bioinformatics Hub, Brigham and Women's Hospital, Boston, MA 02115.
  • Dong X; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115.
  • Feany MB; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
bioRxiv ; 2024 Feb 04.
Article en En | MEDLINE | ID: mdl-38352559
ABSTRACT
Missense mutations in the gene encoding the microtubule-associated protein tau cause autosomal dominant forms of frontotemporal dementia. Multiple models of frontotemporal dementia based on transgenic expression of human tau in experimental model organisms, including Drosophila, have been described. These models replicate key features of the human disease, but do not faithfully recreate the genetic context of the human disorder. Here we use CRISPR-Cas mediated gene editing to model frontotemporal dementia caused by the tau P301L mutation by creating the orthologous mutation, P251L, in the endogenous Drosophila tau gene. Flies heterozygous or homozygous for tau P251L display age-dependent neurodegeneration, metabolic defects and accumulate DNA damage in affected neurons. To understand the molecular events promoting neuronal dysfunction and death in knock-in flies we performed single-cell RNA sequencing on approximately 130,000 cells from brains of tau P251L mutant and control flies. We found that expression of disease-associated mutant tau altered gene expression cell autonomously in all neuronal cell types identified and non-cell autonomously in glial cells. Cell signaling pathways, including glial-neuronal signaling, were broadly dysregulated as were brain region and cell-type specific protein interaction networks and gene regulatory programs. In summary, we present here a genetic model of tauopathy, which faithfully recapitulates the genetic context and phenotypic features of the human disease and use the results of comprehensive single cell sequencing analysis to outline pathways of neurotoxicity and highlight the role of non-cell autonomous changes in glia.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos