title: A neuroprotective phase precedes striatal degeneration upon nucleolar stress.
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.
authors.affiliation: 1] Department of Molecular Biology of the Cell I, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany [2] Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland.
authors.forename: G
authors.initials: G
authors.lastname: Kreiner
authors.forename: H
authors.initials: H
authors.lastname: Bierhoff
authors.forename: M
authors.initials: M
authors.lastname: Armentano
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Parkitna
authors.forename: K
authors.initials: K
authors.lastname: Sowodniok
authors.forename: J R
authors.initials: JR
authors.lastname: Naranjo
authors.forename: L
authors.initials: L
authors.lastname: Bonfanti
authors.forename: B
authors.initials: B
authors.lastname: Liss
authors.forename: G
authors.initials: G
authors.lastname: Schütz
authors.forename: I
authors.initials: I
authors.lastname: Grummt
authors.forename: R
authors.initials: R
authors.lastname: Parlato
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism / Q000473:pathology*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse