C9orf72-associated neurodegeneration in ALS-FTD: breaking new ground in ribosomal RNA and nucleolar dysfunction

Review
  • 81 Downloads

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are neurodegenerative diseases with distinct clinical appearance. However, both share as major genetic risk factor a C9orf72 locus intronic hexanucleotide expansion. The pathogenic pathways associated with the expansion-dependent neuronal toxicity are still poorly understood. Recent efforts to identify common threads of neuronal dysfunction have pointed towards deficits of ribosomal RNA (rRNA) biogenesis and loss of nucleolar integrity, a condition known as nucleolar stress that is an emerging shared feature among neurodegenerative diseases. Intriguingly, the C9orf72 mutation in ALS-FTD interferes with the function of the nucleolus by transcripts and dipeptide repeats (DPRs) produced by the hexanucleotide expansion. Experimental discrepancies have given rise to different hypotheses with regard to the connection of C9orf72 and nucleolar activity. In this review, we present and discuss emerging concepts concerning the impact of C9orf72 expansion on nucleolar biology. Moreover, we discuss the “nucleolar stress hypothesis,” according to which nucleolar malfunction accompanies, exacerbates, or potentially triggers a degenerative phenotype. Upcoming awareness of the involvement of nucleolar stress in C9orf72 ALS-FTD could shed light into its pathogenesis, enabling potential treatment options aimed at shielding an “Achilles’ heel” of neurons.

Keywords

Neurodegeneration Nucleolus Dipeptide repeats rRNA Stress response 

References

  1. Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW 3rd, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646CrossRefPubMedPubMedCentralGoogle Scholar
  2. Baborie A, Griffiths TD, Jaros E, Perry R, McKeith IG, Burn DJ, Masuda-Suzukake M, Hasegawa M, Rollinson S, Pickering-Brown S, Robinson AC, Davidson YS, Mann DM (2015) Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene. Neuropathol Appl Neurobiol 41:601–612CrossRefPubMedPubMedCentralGoogle Scholar
  3. Belzil VV, Bauer PO, Prudencio M, Gendron TF, Stetler CT, Yan IK, Pregent L, Daughrity L, Baker MC, Rademakers R, Boylan K, Patel TC, Dickson DW, Petrucelli L (2013) Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 126:895–905CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bendotti C, Marino M, Cheroni C, Fontana E, Crippa V, Poletti A, De Biasi S (2012) Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Prog Neurobiol 97:101–126CrossRefPubMedGoogle Scholar
  5. Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, Guharoy M, De Decker M, Jaspers T, Ryan VH, Janke AM, Baatsen P, Vercruysse T, Kolaitis RM, Daelemans D, Taylor JP, Kedersha N, Anderson P, Impens F, Sobott F, Schymkowitz J, Rousseau F, Fawzi NL, Robberecht W, Van Damme P, Tompa P, Van Den Bosch L (2017) Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol Cell 65:1044–1055 e1045CrossRefPubMedPubMedCentralGoogle Scholar
  6. Boulon S, Westman BJ, Hutten S, Boisvert FM, Lamond AI (2010) The nucleolus under stress. Mol Cell 40:216–227CrossRefPubMedPubMedCentralGoogle Scholar
  7. Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K (2013) Amyotrophic lateral sclerosis—a model of corticofugal axonal spread. Nat Rev Neurol 9:708–714CrossRefPubMedPubMedCentralGoogle Scholar
  8. Brockington A, Ning K, Heath PR, Wood E, Kirby J, Fusi N, Lawrence N, Wharton SB, Ince PG, Shaw PJ (2013) Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathol 125:95–109CrossRefPubMedGoogle Scholar
  9. Bubulya PA, Prasanth KV, Deerinck TJ, Gerlich D, Beaudouin J, Ellisman MH, Ellenberg J, Spector DL (2004) Hypophosphorylated SR splicing factors transiently localize around active nucleolar organizing regions in telophase daughter nuclei. J Cell Biol 167:51–63CrossRefPubMedPubMedCentralGoogle Scholar
  10. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, Heverin M, Jordan N, Kenna K, Lynch C, McLaughlin RL, Iyer PM, O'Brien C, Phukan J, Wynne B, Bokde AL, Bradley DG, Pender N, Al-Chalabi A, Hardiman O (2012) Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 11:232–240CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cacace R, Van Cauwenberghe C, Bettens K, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Baumer V, Dillen L, Mattheijssens M, Peeters K, Cruts M, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Sleegers K (2013) C9orf72 G4C2 repeat expansions in Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 34(1712):e1711–e1717Google Scholar
  12. Cerami C, Scarpini E, Cappa SF, Galimberti D (2012) Frontotemporal lobar degeneration: current knowledge and future challenges. J Neurol 259:2278–2286CrossRefPubMedGoogle Scholar
  13. Chen S, Zhang X, Song L, Le W (2012) Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol 22:110–116CrossRefPubMedGoogle Scholar
  14. Ciura S, Lattante S, Le Ber I, Latouche M, Tostivint H, Brice A, Kabashi E (2013) Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 74:180–187PubMedGoogle Scholar
  15. Cong R, Das S, Ugrinova I, Kumar S, Mongelard F, Wong J, Bouvet P (2012) Interaction of nucleolin with ribosomal RNA genes and its role in RNA polymerase I transcription. Nucleic Acids Res 40:9441–9454CrossRefPubMedPubMedCentralGoogle Scholar
  16. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256CrossRefPubMedPubMedCentralGoogle Scholar
  17. Domanskyi A, Geissler C, Vinnikov IA, Alter H, Schober A, Vogt MA, Gass P, Parlato R, Schutz G (2011) Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson’s disease models. FASEB J 25:2898–2910CrossRefPubMedGoogle Scholar
  18. Evsyukov V, Domanskyi A, Bierhoff H, Gispert S, Mustafa R, Schlaudraff F, Liss B, Parlato R (2017) Genetic mutations linked to Parkinson’s disease differentially control nucleolar activity in pre-symptomatic mouse models. Dis Model Mech 10:633–643CrossRefPubMedPubMedCentralGoogle Scholar
  19. Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V, Halloran MA, Gleeson PA, Blair IP, Soo KY, King AE, Atkin JD (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23:3579–3595CrossRefPubMedPubMedCentralGoogle Scholar
  20. Farg MA, Konopka A, Soo KY, Ito D, Atkin JD (2017) The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis. Hum Mol Genet 26:2882–2896CrossRefPubMedGoogle Scholar
  21. Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EM, Parkinson G, Isaacs AM (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2:1016CrossRefPubMedPubMedCentralGoogle Scholar
  22. Fumagalli S, Di Cara A, Neb-Gulati A, Natt F, Schwemberger S, Hall J, Babcock GF, Bernardi R, Pandolfi PP, Thomas G (2009) Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction. Nat Cell Biol 11:501–508CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gao FB, Almeida S, Lopez-Gonzalez R (2017) Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. EMBO J 36:2931–2950CrossRefPubMedGoogle Scholar
  24. Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T, Daughrity L, Dunmore JH, Castanedes-Casey M, Chew J, Cosio DM, van Blitterswijk M, Lee WC, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844CrossRefPubMedPubMedCentralGoogle Scholar
  25. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Baumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54–65CrossRefPubMedGoogle Scholar
  26. Gjerset RA, Bandyopadhyay K (2006) Regulation of p14ARF through subnuclear compartmentalization. Cell Cycle 5:686–690CrossRefPubMedGoogle Scholar
  27. Grummt I (2013) The nucleolus-guardian of cellular homeostasis and genome integrity. Chromosoma 122:487–497CrossRefPubMedGoogle Scholar
  28. Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507:195–200CrossRefPubMedPubMedCentralGoogle Scholar
  29. Haeusler AR, Donnelly CJ, Rothstein JD (2016) The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat Rev Neurosci 17:383–395CrossRefPubMedGoogle Scholar
  30. Hetman M, Pietrzak M (2012) Emerging roles of the neuronal nucleolus. Trends Neurosci 35:305–314CrossRefPubMedPubMedCentralGoogle Scholar
  31. Jara JH, Genc B, Cox GA, Bohn MC, Roos RP, Macklis JD, Ulupinar E, Ozdinler PH (2015) Corticospinal motor neurons are susceptible to increased ER stress and display profound degeneration in the absence of UCHL1 function. Cereb Cortex 25:4259–4272CrossRefPubMedPubMedCentralGoogle Scholar
  32. Jesse S, Bayer H, Alupei MC, Zugel M, Mulaw M, Tuorto F, Malmsheimer S, Singh K, Steinacker J, Schumann U, Ludolph AC, Scharffetter-Kochanek K, Witting A, Weydt P, Iben S (2017) Ribosomal transcription is regulated by PGC-1alpha and disturbed in Huntington’s disease. Sci Rep 7:8513CrossRefPubMedPubMedCentralGoogle Scholar
  33. Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18:1226–1229CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kang H, Shin JH (2015) Repression of rRNA transcription by PARIS contributes to Parkinson’s disease. Neurobiol Dis 73:220–228CrossRefPubMedGoogle Scholar
  35. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473CrossRefPubMedPubMedCentralGoogle Scholar
  36. Kiryk A, Sowodniok K, Kreiner G, Rodriguez-Parkitna J, Sonmez A, Gorkiewicz T, Bierhoff H, Wawrzyniak M, Janusz AK, Liss B, Konopka W, Schutz G, Kaczmarek L, Parlato R (2013) Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons. Front Cell Neurosci 7:207CrossRefPubMedPubMedCentralGoogle Scholar
  37. Koppers M, Blokhuis AM, Westeneng HJ, Terpstra ML, Zundel CA, Vieira de Sa R, Schellevis RD, Waite AJ, Blake DJ, Veldink JH, van den Berg LH, Pasterkamp RJ (2015) C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 78:426–438CrossRefPubMedPubMedCentralGoogle Scholar
  38. Kostic VS, Dobricic V, Stankovic I, Ralic V, Stefanova E (2014) C9orf72 expansion as a possible genetic cause of Huntington disease phenocopy syndrome. J Neurol 261:1917–1921CrossRefPubMedGoogle Scholar
  39. Kreiner G, Bierhoff H, Armentano M, Rodriguez-Parkitna J, Sowodniok K, Naranjo JR, Bonfanti L, Liss B, Schutz G, Grummt I, Parlato R (2013) A neuroprotective phase precedes striatal degeneration upon nucleolar stress. Cell Death Differ 20:1455–1464CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, Kim J, Yun J, Xie Y, McKnight SL (2014) Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345:1139–1145CrossRefPubMedPubMedCentralGoogle Scholar
  41. Larsen DH, Stucki M (2016) Nucleolar responses to DNA double-strand breaks. Nucleic Acids Res 44:538–544CrossRefPubMedGoogle Scholar
  42. Lee C, Smith BA, Bandyopadhyay K, Gjerset RA (2005) DNA damage disrupts the p14ARF-B23(nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF. Cancer Res 65:9834–9842CrossRefPubMedGoogle Scholar
  43. Lee J, Hwang YJ, Ryu H, Kowall NW, Ryu H (2014) Nucleolar dysfunction in Huntington’s disease. Biochim Biophys Acta 1842:785–790CrossRefPubMedGoogle Scholar
  44. Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, Cika J, Coughlin M, Messing J, Molliex A, Maxwell BA, Kim NC, Temirov J, Moore J, Kolaitis RM, Shaw TI, Bai B, Peng J, Kriwacki RW, Taylor JP (2016) C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167:774–788 e717CrossRefPubMedPubMedCentralGoogle Scholar
  45. Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ (2013) The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29:499–503CrossRefPubMedPubMedCentralGoogle Scholar
  46. Ludolph AC, Brettschneider J, Weishaupt JH (2012) Amyotrophic lateral sclerosis. Curr Opin Neurol 25:530–535CrossRefPubMedGoogle Scholar
  47. Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K, Weng SM, Haass C, Kretzschmar HA, Edbauer D, Neumann M (2013) Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 126:859–879CrossRefPubMedGoogle Scholar
  48. Majounie E, Renton AE, Mok K, Dopper EGP, Waite A, Rollinson S, Chio A, Restagno G, Nicolaou N, Simon-Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Foris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering-Brown S, Traynor BJ, Consortium C-AF, ALS FRNFF, Consortium I (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323–330CrossRefPubMedPubMedCentralGoogle Scholar
  49. Marquez-Lona EM, Tan Z, Schreiber SS (2012) Nucleolar stress characterized by downregulation of nucleophosmin: a novel cause of neuronal degeneration. Biochem Biophys Res Commun 417:514–520CrossRefPubMedGoogle Scholar
  50. Mayer C, Grummt I (2005) Cellular stress and nucleolar function. Cell Cycle 4:1036–1038CrossRefPubMedGoogle Scholar
  51. McGoldrick P, Joyce PI, Fisher EM, Greensmith L (2013) Rodent models of amyotrophic lateral sclerosis. Biochim Biophys Acta 1832:1421–1436CrossRefPubMedGoogle Scholar
  52. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19:4439–4448CrossRefPubMedPubMedCentralGoogle Scholar
  53. Mitrea DM, Cika JA, Guy CS, Ban, D., Banerjee PR, Stanley CB, Nourse A, Deniz AA, Kriwacki RW (2016) Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. Elife 5:e13571Google Scholar
  54. Mizielinska S, Gronke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IOC, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EMC, Partridge L, Isaacs AM (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345:1192–1194CrossRefPubMedPubMedCentralGoogle Scholar
  55. Mizielinska S, Ridler CE, Balendra R, Thoeng A, Woodling NS, Grasser FA, Plagnol V, Lashley T, Partridge L, Isaacs AM (2017) Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathol Commun 5:29CrossRefPubMedPubMedCentralGoogle Scholar
  56. Moens TG, Partridge L, Isaacs AM (2017) Genetic models of C9orf72: what is toxic? Curr Opin Genet Dev 44:92–101CrossRefPubMedGoogle Scholar
  57. Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, Haass C, Edbauer D (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338CrossRefPubMedGoogle Scholar
  58. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133CrossRefPubMedGoogle Scholar
  59. O’Rourke JG, Bogdanik L, Muhammad AK, Gendron TF, Kim KJ, Austin A, Cady J, Liu EY, Zarrow J, Grant S, Ho R, Bell S, Carmona S, Simpkinson M, Lall D, Wu K, Daughrity L, Dickson DW, Harms MB, Petrucelli L, Lee EB, Lutz CM, Baloh RH (2015) C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88:892–901CrossRefPubMedPubMedCentralGoogle Scholar
  60. Parlato R, Bierhoff H (2015) Role of nucleolar dysfunction in neurodegenerative disorders: a game of genes? AIMS Molecular Science 2:211–224CrossRefGoogle Scholar
  61. Parlato R, Kreiner G (2013) Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle? J Mol Med (Berl) 91:541–547CrossRefGoogle Scholar
  62. Parlato R, Liss B (2014) How Parkinson’s disease meets nucleolar stress. Biochim Biophys Acta 1842:791–797CrossRefPubMedGoogle Scholar
  63. Parlato R, Kreiner G, Erdmann G, Rieker C, Stotz S, Savenkova E, Berger S, Grummt I, Schutz G (2008) Activation of an endogenous suicide response after perturbation of rRNA synthesis leads to neurodegeneration in mice. J Neurosci 28:12759–12764CrossRefPubMedGoogle Scholar
  64. Paul JW, Gitler AD (2014) Cell biology. Clogging information flow in ALS. Science 345:1118–1119CrossRefPubMedGoogle Scholar
  65. Polymenidou M, Cleveland DW (2011) The seeds of neurodegeneration: prion-like spreading in ALS. Cell 147:498–508CrossRefPubMedPubMedCentralGoogle Scholar
  66. Reddy K, Zamiri B, Stanley SY, Macgregor RB Jr, Pearson CE (2013) The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J Biol Chem 288:9860–9866CrossRefPubMedPubMedCentralGoogle Scholar
  67. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Consortium I, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268CrossRefPubMedPubMedCentralGoogle Scholar
  68. Rieker C, Engblom D, Kreiner G, Domanskyi A, Schober A, Stotz S, Neumann M, Yuan X, Grummt I, Schutz G, Parlato R (2011) Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling. J Neurosci 31:453–460CrossRefPubMedGoogle Scholar
  69. Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14:248–264CrossRefPubMedGoogle Scholar
  70. Rubbi CP, Milner J (2003) Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J 22:6068–6077CrossRefPubMedPubMedCentralGoogle Scholar
  71. Schludi MH, May S, Grasser FA, Rentzsch K, Kremmer E, Kupper C, Klopstock T, German Consortium for Frontotemporal Lobar, D., Bavarian Brain Banking, A, Arzberger T, Edbauer D (2015) Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol 130:537–555CrossRefPubMedPubMedCentralGoogle Scholar
  72. Shu L, Sun Q, Zhang Y, Xu Q, Guo J, Yan X, Tang B (2016) The association between C9orf72 repeats and risk of Alzheimer's disease and amyotrophic lateral sclerosis: a meta-analysis. Parkinsons Dis 2016:5731734PubMedPubMedCentralGoogle Scholar
  73. Sicot G, Gomes-Pereira M (2013) RNA toxicity in human disease and animal models: from the uncovering of a new mechanism to the development of promising therapies. Biochim Biophys Acta 1832:1390–1409CrossRefPubMedGoogle Scholar
  74. Suzuki N, Maroof AM, Merkle FT, Koszka K, Intoh A, Armstrong I, Moccia R, Davis-Dusenbery BN, Eggan K (2013) The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. Nat Neurosci 16:1725–1727CrossRefPubMedPubMedCentralGoogle Scholar
  75. Tao Z, Wang H, Xia Q, Li K, Li K, Jiang X, Xu G, Wang G, Ying Z (2015) Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet 24:2426–2441CrossRefPubMedGoogle Scholar
  76. Tapia O, Narcis JO, Riancho J, Tarabal O, Piedrafita L, Caldero J, Berciano MT, Lafarga M (2017) Cellular bases of the RNA metabolism dysfunction in motor neurons of a murine model of spinal muscular atrophy: role of Cajal bodies and the nucleolus. Neurobiol Dis 108:83–99CrossRefPubMedGoogle Scholar
  77. Taylor JP, Brown RH Jr, Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539:197–206CrossRefPubMedPubMedCentralGoogle Scholar
  78. Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao FB (2015) Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a drosophila model of C9ORF72 FTD/ALS. Neuron 87:1207–1214CrossRefPubMedPubMedCentralGoogle Scholar
  79. Tsoi H, Chan HY (2014) Roles of the nucleolus in the CAG RNA-mediated toxicity. Biochim Biophys Acta 1842:779–784CrossRefPubMedGoogle Scholar
  80. Tsoi H, Lau TC, Tsang SY, Lau KF, Chan HY (2012) CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci U S A 109:13428–13433CrossRefPubMedPubMedCentralGoogle Scholar
  81. Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12:310–322CrossRefPubMedPubMedCentralGoogle Scholar
  82. Vilotti S, Codrich M, Dal Ferro M, Pinto M, Ferrer I, Collavin L, Gustincich S, Zucchelli S (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:e35051CrossRefPubMedPubMedCentralGoogle Scholar
  83. Waite AJ, Baumer D, East S, Neal J, Morris HR, Ansorge O, Blake DJ (2014) Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 35:1779.e5–1779.e13Google Scholar
  84. Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W, Lukashchuk V, Chiang SC, Ray S, Mulcahy PJ, Jurga M, Tsagakis I, Iannitti T, Chandran J, Coldicott I, De Vos KJ, Hassan MK, Higginbottom A, Shaw PJ, Hautbergue GM, Azzouz M, El-Khamisy SF (2017) C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci 20:1225–1235CrossRefPubMedPubMedCentralGoogle Scholar
  85. Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y, Lin S, Shneider NA, Monaghan J, Pandey UB, Pasinelli P, Ichida JK, Trotti D (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 84:1213–1225CrossRefPubMedPubMedCentralGoogle Scholar
  86. Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, Sato C, Zheng Y, Ghani M, Dib S, Keith J, Robertson J, Rogaeva E (2013) Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 92:981–989CrossRefPubMedPubMedCentralGoogle Scholar
  87. Yao Z, Duan S, Hou D, Wang W, Wang G, Liu Y, Wen L, Wu M (2010) B23 acts as a nucleolar stress sensor and promotes cell survival through its dynamic interaction with hnRNPU and hnRNPA1. Oncogene 29:1821–1834CrossRefPubMedGoogle Scholar
  88. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56–61CrossRefPubMedPubMedCentralGoogle Scholar
  89. Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, Ostrow LW, Rothstein JD, Troncoso JC, Ranum LP (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A 110:E4968–E4977CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Anatomy and Medical Cell BiologyUniversity of HeidelbergHeidelbergGermany
  2. 2.Wolfson Institute for Biomedical ResearchUniversity College LondonLondonUK
  3. 3.Institute of Applied PhysiologyUniversity of UlmUlmGermany

Personalised recommendations