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The Journal of Neuroscience, November 26, 2008, 28(48):12759-12764; doi:10.1523/JNEUROSCI.2439-08.2008

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Brief Communications
Activation of an Endogenous Suicide Response after Perturbation of rRNA Synthesis Leads to Neurodegeneration in Mice

Rosanna Parlato,¹ Grzegorz Kreiner,¹ Gitta Erdmann,¹ Claus Rieker,¹ Stefanie Stotz,¹ Ella Savenkova,¹ Stefan Berger,¹ Ingrid Grummt,² and Günther Schütz¹

¹Division of Molecular Biology of the Cell I and ²Division of Molecular Biology of the Cell II, German Cancer Research Center, Deutsches Krebsforschungszentrum–Zentrum für Molekulare Biologie der Universität Heidelberg Alliance, D-69120 Heidelberg, Germany

Correspondence should be addressed to Dr. Günther Schütz, Division of Molecular Biology of the Cell I, German Cancer Research Center, D-69120 Heidelberg, Germany. Email: g.schuetz{at}dkfz.de

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.

Key words: survival; rRNA transcription; neural progenitors; hippocampus; degeneration; nucleolus

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Received May 30, 2008; revised Aug. 19, 2008; accepted Oct. 8, 2008.

Correspondence should be addressed to Dr. Günther Schütz, Division of Molecular Biology of the Cell I, German Cancer Research Center, D-69120 Heidelberg, Germany. Email: g.schuetz{at}dkfz.de

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