title: Activation of an endogenous suicide response after perturbation of rRNA synthesis leads to neurodegeneration in mice.
abstract: Transcription of rRNA genes is essential for maintaining nucleolar integrity, a hallmark for the healthy state and proliferation rate of a cell. Inhibition of rRNA synthesis leads to disintegration of the nucleolus, elevated levels of p53, and induction of cell suicide, identifying the nucleolus as a critical stress sensor. Whether deregulation of rRNA synthesis is causally involved in neurodegeneration by promoting cell death and/or by inhibiting cellular growth has however not been addressed. The transcription factor TIF-IA plays a central role in mammalian rRNA synthesis, regulating the transcriptional activity of RNA polymerase I. To investigate the consequences of nucleolar perturbation in the nervous system, we have chosen to specifically ablate the gene encoding the transcription factor TIF-IA in two different contexts: neural progenitors and hippocampal neurons. Here, we show that ablation of TIF-IA leads to impaired nucleolar activity and results in increased levels of the proapoptotic transcription factor p53 in both neural progenitors and hippocampal neurons but induces rapid apoptosis only in neural progenitors. Nondividing cells of the adult hippocampus are more refractory to loss of rRNA transcription and face a protracted degeneration. Our study provides an unexploited strategy to initiate neurodegeneration based on perturbation of nucleolar function and underscores a novel perspective to study the cellular and molecular changes involved in the neurodegenerative processes.
authors.affiliation: Division of Molecular Biology of the Cell I, German Cancer Research Center, Deutsches Krebsforschungszentrum-Zentrum für Molekulare Biologie der Universität Heidelberg Alliance, D-69120 Heidelberg, Germany.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parlato
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kreiner
authors.forename: Gitta
authors.initials: G
authors.lastname: Erdmann
authors.forename: Claus
authors.initials: C
authors.lastname: Rieker
authors.forename: Stefanie
authors.initials: S
authors.lastname: Stotz
authors.forename: Ella
authors.initials: E
authors.lastname: Savenkova
authors.forename: Stefan
authors.initials: S
authors.lastname: Berger
authors.forename: Ingrid
authors.initials: I
authors.lastname: Grummt
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055495:Neurogenesis / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000502:physiology*; D012335:RNA, Ribosomal / Q000096:biosynthesis* / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53