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Role of nucleolar dysfunction in neurodegenerative disorders: a game of genes?

  • Received: 15 April 2015 Accepted: 26 May 2015 Published: 29 May 2015
  • Within the cell nucleus the nucleolus is the site of rRNA transcription and ribosome biogenesis and its activity is clearly essential for a correct cell function, however its specific role in neuronal homeostasis remains mainly unknown. Here we review recent evidence that impaired nucleolar activity is a common mechanism in different neurodegenerative disorders. We focus on the specific causes and consequences of impaired nucleolar activity to better understand the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). In particular, we discuss the genetic and epigenetic factors that might regulate nucleolar function in these diseases. In addition, we describe novel animal models enabling the dissection of the context-specific series of events triggered by nucleolar disruption, also known as nucleolar stress. Finally, we suggest how this novel mechanism could help to identify strategies to treat these still incurable disorders.

    Citation: Rosanna Parlato, Holger Bierhoff. Role of nucleolar dysfunction in neurodegenerative disorders: a game of genes?[J]. AIMS Molecular Science, 2015, 2(3): 211-224. doi: 10.3934/molsci.2015.3.211

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  • Within the cell nucleus the nucleolus is the site of rRNA transcription and ribosome biogenesis and its activity is clearly essential for a correct cell function, however its specific role in neuronal homeostasis remains mainly unknown. Here we review recent evidence that impaired nucleolar activity is a common mechanism in different neurodegenerative disorders. We focus on the specific causes and consequences of impaired nucleolar activity to better understand the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). In particular, we discuss the genetic and epigenetic factors that might regulate nucleolar function in these diseases. In addition, we describe novel animal models enabling the dissection of the context-specific series of events triggered by nucleolar disruption, also known as nucleolar stress. Finally, we suggest how this novel mechanism could help to identify strategies to treat these still incurable disorders.


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    [1] Boulon S, Westman BJ, Hutten S, et al. (2010) The nucleolus under stress. Mol Cell 40: 216-227. doi: 10.1016/j.molcel.2010.09.024
    [2] Mayer C, Grummt I (2005) Cellular stress and nucleolar function. Cell Cycle 4: 1036-1038. doi: 10.4161/cc.4.8.1925
    [3] Grummt I (2013) The nucleolus-guardian of cellular homeostasis and genome integrity. Chromosoma 122: 487-497. doi: 10.1007/s00412-013-0430-0
    [4] Rubbi CP, Milner J (2003) Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. Embo J 22: 6068-6077. doi: 10.1093/emboj/cdg579
    [5] Hetman M, Pietrzak M (2012) Emerging roles of the neuronal nucleolus. Trends Neurosci 35: 305-314. doi: 10.1016/j.tins.2012.01.002
    [6] Parlato R, Kreiner G (2013) Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle? J Mol Med (Berl) 91: 541-547. doi: 10.1007/s00109-012-0981-1
    [7] Haeusler AR, Donnelly CJ, Periz G, et al. (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507: 195-200. doi: 10.1038/nature13124
    [8] Chan HY (2014) RNA-mediated pathogenic mechanisms in polyglutamine diseases and amyotrophic lateral sclerosis. Front Cell Neurosci 8: 431.
    [9] Rohrer JD, Isaacs AM, Mizielinska S, et al. (2015) C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol 14: 291-301. doi: 10.1016/S1474-4422(14)70233-9
    [10] Kwon I, Xiang S, Kato M, et al. (2014) Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345: 1139-1145. doi: 10.1126/science.1254917
    [11] Wen X, Tan W, Westergard T, et al. (2014) Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84: 1213-1225. doi: 10.1016/j.neuron.2014.12.010
    [12] Tao Z, Wang H, Xia Q, et al. (2015) Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet 24: 2426-2441. doi: 10.1093/hmg/ddv005
    [13] Riancho J, Ruiz-Soto M, Villagra NT, et al. (2014) Compensatory Motor Neuron Response to Chromatolysis in the Murine hSOD1(G93A) Model of Amyotrophic Lateral Sclerosis. Front Cell Neurosci 8: 346.
    [14] Palanca A, Casafont I, Berciano MT, et al. (2014) Reactive nucleolar and Cajal body responses to proteasome inhibition in sensory ganglion neurons. Biochim Biophys Acta 1842: 848-859. doi: 10.1016/j.bbadis.2013.11.016
    [15] Cong R, Das S, Ugrinova I, et al. (2012) Interaction of nucleolin with ribosomal RNA genes and its role in RNA polymerase I transcription. Nucleic Acids Res 40: 9441-9454. doi: 10.1093/nar/gks720
    [16] Tsoi H, Lau TC, Tsang SY, et al. (2012) CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci U S A 109: 13428-13433. doi: 10.1073/pnas.1204089109
    [17] Tsoi H, Chan HY (2013) Expression of expanded CAG transcripts triggers nucleolar stress in Huntington's disease. Cerebellum 12: 310-312. doi: 10.1007/s12311-012-0447-6
    [18] Ross CA, Tabrizi SJ (2011) Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10: 83-98. doi: 10.1016/S1474-4422(10)70245-3
    [19] Lee J, Hwang YJ, Ryu H, et al. (2014) Nucleolar dysfunction in Huntington's disease. Biochim Biophys Acta 1842: 785-790. doi: 10.1016/j.bbadis.2013.09.017
    [20] Kreiner G, Bierhoff H, Armentano M, et al. (2013) A neuroprotective phase precedes striatal degeneration upon nucleolar stress. Cell Death Differ 20: 1455-1464. doi: 10.1038/cdd.2013.66
    [21] Lee J, Hwang YJ, Boo JH, et al. (2011) Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington's disease. Cell Death Differ 18: 1726-1735. doi: 10.1038/cdd.2011.38
    [22] Hwang YJ, Han D, Kim KY, et al. (2014) ESET methylates UBF at K232/254 and regulates nucleolar heterochromatin plasticity and rDNA transcription. Nucleic Acids Res 42: 1628-1643. doi: 10.1093/nar/gkt1041
    [23] Lee J, Hwang YJ, Kim KY, et al. (2013) Epigenetic mechanisms of neurodegeneration in Huntington's disease. Neurotherapeutics 10: 664-676. doi: 10.1007/s13311-013-0206-5
    [24] Ammal Kaidery N, Tarannum S, Thomas B (2013) Epigenetic landscape of Parkinson's disease: emerging role in disease mechanisms and therapeutic modalities. Neurotherapeutics 10: 698-708. doi: 10.1007/s13311-013-0211-8
    [25] Masliah E, Dumaop W, Galasko D, et al. (2013) Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics 8: 1030-1038. doi: 10.4161/epi.25865
    [26] Healy-Stoffel M, Ahmad SO, Stanford JA, et al. (2013) Altered nucleolar morphology in substantia nigra dopamine neurons following 6-hydroxydopamine lesion in rats. Neurosci Lett 546: 26-30. doi: 10.1016/j.neulet.2013.04.033
    [27] Healy-Stoffel M, Omar Ahmad S, Stanford JA, et al. (2014) Differential effects of intrastriatal 6-hydroxydopamine on cell number and morphology in midbrain dopaminergic subregions of the rat. Brain Res 1574: 113-119. doi: 10.1016/j.brainres.2014.05.045
    [28] Rieker C, Engblom D, Kreiner G, et al. (2011) Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling. J Neurosci 31: 453-460. doi: 10.1523/JNEUROSCI.0590-10.2011
    [29] Kang H, Shin JH (2014) Repression of rRNA transcription by PARIS contributes to Parkinson's disease. Neurobiol Dis 73C: 220-228.
    [30] Vilotti S, Codrich M, Dal Ferro M, et al. (2012) Parkinson's Disease DJ-1 L166P Alters rRNA Biogenesis by Exclusion of TTRAP from the Nucleolus and Sequestration into Cytoplasmic Aggregates via TRAF6. PLoS One 7: e35051. doi: 10.1371/journal.pone.0035051
    [31] Vilotti S, Biagioli M, Foti R, et al. (2012) The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition. Cell Death Differ 19: 488-500. doi: 10.1038/cdd.2011.118
    [32] Iacono D, O'Brien R, Resnick SM, et al. (2008) Neuronal hypertrophy in asymptomatic Alzheimer disease. J Neuropathol Exp Neurol 67: 578-589. doi: 10.1097/NEN.0b013e3181772794
    [33] Pietrzak M, Rempala G, Nelson PT, et al. (2011) Epigenetic Silencing of Nucleolar rRNA Genes in Alzheimer's Disease. PLoS One 6: e22585. doi: 10.1371/journal.pone.0022585
    [34] da Silva AM, Payao SL, Borsatto B, et al. (2000) Quantitative evaluation of the rRNA in Alzheimer's disease. Mech Ageing Dev 120: 57-64. doi: 10.1016/S0047-6374(00)00180-9
    [35] McStay B, Grummt I (2008) The epigenetics of rRNA genes: from molecular to chromosome biology. Annu Rev Cell Dev Biol 24: 131-157. doi: 10.1146/annurev.cellbio.24.110707.175259
    [36] Strohner R, Nemeth A, Jansa P, et al. (2001) NoRC--a novel member of mammalian ISWI-containing chromatin remodeling machines. EMBO J 20: 4892-4900. doi: 10.1093/emboj/20.17.4892
    [37] Mayer C, Schmitz KM, Li J, et al. (2006) Intergenic transcripts regulate the epigenetic state of rRNA genes. Mol Cell 22: 351-361. doi: 10.1016/j.molcel.2006.03.028
    [38] Santoro R, Li J, Grummt I (2002) The nucleolar remodeling complex NoRC mediates heterochromatin formation and silencing of ribosomal gene transcription. Nat Genet 32: 393-396. doi: 10.1038/ng1010
    [39] Gu L, Frommel SC, Oakes CC, et al. (2015) BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence. Nat Genet 47: 22-30.
    [40] Wu P, Zuo X, Deng H, et al. (2013) Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res Bull 97: 69-80. doi: 10.1016/j.brainresbull.2013.06.001
    [41] Santoro R, Schmitz KM, Sandoval J, et al. (2010) Intergenic transcripts originating from a subclass of ribosomal DNA repeats silence ribosomal RNA genes in trans. EMBO Rep 11: 52-58. doi: 10.1038/embor.2009.254
    [42] Wan J, Yourshaw M, Mamsa H, et al. (2012) Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet 44: 704-708. doi: 10.1038/ng.2254
    [43] Bierhoff H, Dammert MA, Brocks D, et al. (2014) Quiescence-induced LncRNAs trigger H4K20 trimethylation and transcriptional silencing. Mol Cell 54: 675-682. doi: 10.1016/j.molcel.2014.03.032
    [44] Evertts AG, Manning AL, Wang X, et al. (2013) H4K20 methylation regulates quiescence and chromatin compaction. Mol Biol Cell 24: 3025-3037. doi: 10.1091/mbc.E12-07-0529
    [45] Sarg B, Koutzamani E, Helliger W, et al. (2002) Postsynthetic trimethylation of histone H4 at lysine 20 in mammalian tissues is associated with aging. J Biol Chem 277: 39195-39201. doi: 10.1074/jbc.M205166200
    [46] Shumaker DK, Dechat T, Kohlmaier A, et al. (2006) Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A 103: 8703-8708. doi: 10.1073/pnas.0602569103
    [47] Bierhoff H, Schmitz K, Maass F, et al. (2010) Noncoding transcripts in sense and antisense orientation regulate the epigenetic state of ribosomal RNA genes. Cold Spring Harb Symp Quant Biol 75: 357-364. doi: 10.1101/sqb.2010.75.060
    [48] Murayama A, Ohmori K, Fujimura A, et al. (2008) Epigenetic control of rDNA loci in response to intracellular energy status. Cell 133: 627-639. doi: 10.1016/j.cell.2008.03.030
    [49] Donmez G, Outeiro TF (2013) SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Mol Med 5: 344-352. doi: 10.1002/emmm.201302451
    [50] Herskovits AZ, Guarente L (2014) SIRT1 in neurodevelopment and brain senescence. Neuron 81: 471-483. doi: 10.1016/j.neuron.2014.01.028
    [51] Li Y, Xu W, McBurney MW, et al. (2008) SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab 8: 38-48. doi: 10.1016/j.cmet.2008.05.004
    [52] Zhang F, Wang S, Gan L, et al. (2011) Protective effects and mechanisms of sirtuins in the nervous system. Prog Neurobiol 95: 373-395. doi: 10.1016/j.pneurobio.2011.09.001
    [53] Smith MR, Syed A, Lukacsovich T, et al. (2014) A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease. Hum Mol Genet 23: 2995-3007. doi: 10.1093/hmg/ddu010
    [54] Schnapp A, Pfleiderer C, Rosenbauer H, et al. (1990) A growth-dependent transcription initiation factor (TIF-IA) interacting with RNA polymerase I regulates mouse ribosomal RNA synthesis. EMBO J 9: 2857-2863.
    [55] Grewal SS, Evans JR, Edgar BA (2007) Drosophila TIF-IA is required for ribosome synthesis and cell growth and is regulated by the TOR pathway. J Cell Biol 179: 1105-1113. doi: 10.1083/jcb.200709044
    [56] Mayer C, Bierhoff H, Grummt I (2005) The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. Genes Dev 19: 933-941. doi: 10.1101/gad.333205
    [57] Hoppe S, Bierhoff H, Cado I, et al. (2009) AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. Proc Natl Acad Sci U S A 106: 17781-17786. doi: 10.1073/pnas.0909873106
    [58] DuRose JB, Scheuner D, Kaufman RJ, et al. (2009) Phosphorylation of eukaryotic translation initiation factor 2alpha coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress. Mol Cell Biol 29: 4295-4307. doi: 10.1128/MCB.00260-09
    [59] Nguyen le XT, Mitchell BS (2013) Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA. Proc Natl Acad Sci U S A 110: 20681-20686. doi: 10.1073/pnas.1313097110
    [60] Kiryk A, Sowodniok K, Kreiner G, et al. (2013) Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons. Front Cell Neurosci 7: 207.
    [61] Shamsi F, Parlato R, Collombat P, et al. (2014) A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells. Cell Cycle 13: 3948-3957. doi: 10.4161/15384101.2014.952176
    [62] Parlato R, Kreiner G, Erdmann G, et al. (2008) Activation of an endogenous suicide response after perturbation of rRNA synthesis leads to neurodegeneration in mice. J Neurosci 28: 12759-12764. doi: 10.1523/JNEUROSCI.2439-08.2008
    [63] Domanskyi A, Geissler C, Vinnikov IA, et al. (2011) Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models. FASEB J 25: 2898-2910. doi: 10.1096/fj.11-181958
    [64] Yuan X, Zhou Y, Casanova E, et al. (2005) Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis. Mol Cell 19: 77-87. doi: 10.1016/j.molcel.2005.05.023
    [65] Erickson JD, Bazan NG (2013) The nucleolus fine-tunes the orchestration of an early neuroprotection response in neurodegeneration. Cell Death Differ 20: 1435-1437. doi: 10.1038/cdd.2013.107
    [66] Plotkin JL, Day M, Peterson JD, et al. (2014) Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease. Neuron 83: 178-188. doi: 10.1016/j.neuron.2014.05.032
    [67] Lee JH, Tecedor L, Chen YH, et al. (2015) Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85: 303-315. doi: 10.1016/j.neuron.2014.12.019
    [68] Ravikumar B, Vacher C, Berger Z, et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36: 585-595. doi: 10.1038/ng1362
    [69] Hamdane N, Stefanovsky VY, Tremblay MG, et al. (2014) Conditional inactivation of Upstream Binding Factor reveals its epigenetic functions and the existence of a somatic nucleolar precursor body. PLoS Genet 10: e1004505. doi: 10.1371/journal.pgen.1004505
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