A neuroprotective phase precedes striatal degeneration upon nucleolar stress

G. Kreiner, H. Bierhoff, M. Armentano, J. Rodriguez-Parkitna, K. Sowodniok, J. R. Naranjo, L. Bonfanti, B. Liss, G. Schütz, I. Grummt, R. Parlato

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

The nucleolus is implicated in sensing and responding to cellular stress by stabilizing p53. The pro-apoptotic effect of p53 is associated with several neurodegenerative disorders, including Huntington's disease (HD), which is characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum. Here we show that disruption of nucleolar integrity and function causes nucleolar stress and is an early event in MSNs of R6/2 mice, a transgenic model of HD. Targeted perturbation of nucleolar function in MSNs by conditional knockout of the RNA polymerase I-specific transcription initiation factor IA (TIF-IA) leads to late progressive striatal degeneration, HD-like motor abnormalities and molecular signatures. Significantly, p53 prolongs neuronal survival in TIF-IA-deficient MSNs by transient upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that inhibits mammalian target of rapamycin signaling and induces autophagy. The results emphasize the initial role of nucleolar stress in neurodegeneration and uncover a p53/PTEN-dependent neuroprotective response.

Original languageEnglish (US)
Pages (from-to)1455-1464
Number of pages10
JournalCell death and differentiation
Volume20
Issue number11
DOIs
StatePublished - Nov 1 2013

Fingerprint

Corpus Striatum
Huntington Disease
Neurons
Peptide Initiation Factors
Transcription Factors
RNA Polymerase I
Chromosomes, Human, Pair 10
Autophagy
Sirolimus
Phosphoric Monoester Hydrolases
Neurodegenerative Diseases
Transgenic Mice
Up-Regulation
Neoplasms

Keywords

  • Huntington's disease
  • PTEN
  • neuroprotection
  • nucleolus
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kreiner, G., Bierhoff, H., Armentano, M., Rodriguez-Parkitna, J., Sowodniok, K., Naranjo, J. R., ... Parlato, R. (2013). A neuroprotective phase precedes striatal degeneration upon nucleolar stress. Cell death and differentiation, 20(11), 1455-1464. https://doi.org/10.1038/cdd.2013.66

A neuroprotective phase precedes striatal degeneration upon nucleolar stress. / Kreiner, G.; Bierhoff, H.; Armentano, M.; Rodriguez-Parkitna, J.; Sowodniok, K.; Naranjo, J. R.; Bonfanti, L.; Liss, B.; Schütz, G.; Grummt, I.; Parlato, R.

In: Cell death and differentiation, Vol. 20, No. 11, 01.11.2013, p. 1455-1464.

Research output: Contribution to journalArticle

Kreiner, G, Bierhoff, H, Armentano, M, Rodriguez-Parkitna, J, Sowodniok, K, Naranjo, JR, Bonfanti, L, Liss, B, Schütz, G, Grummt, I & Parlato, R 2013, 'A neuroprotective phase precedes striatal degeneration upon nucleolar stress', Cell death and differentiation, vol. 20, no. 11, pp. 1455-1464. https://doi.org/10.1038/cdd.2013.66
Kreiner G, Bierhoff H, Armentano M, Rodriguez-Parkitna J, Sowodniok K, Naranjo JR et al. A neuroprotective phase precedes striatal degeneration upon nucleolar stress. Cell death and differentiation. 2013 Nov 1;20(11):1455-1464. https://doi.org/10.1038/cdd.2013.66
Kreiner, G. ; Bierhoff, H. ; Armentano, M. ; Rodriguez-Parkitna, J. ; Sowodniok, K. ; Naranjo, J. R. ; Bonfanti, L. ; Liss, B. ; Schütz, G. ; Grummt, I. ; Parlato, R. / A neuroprotective phase precedes striatal degeneration upon nucleolar stress. In: Cell death and differentiation. 2013 ; Vol. 20, No. 11. pp. 1455-1464.
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