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Open Access 01-10-2015 | Original Paper

Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing

Authors: Martin H. Schludi, Stephanie May, Friedrich A. Grässer, Kristin Rentzsch, Elisabeth Kremmer, Clemens Küpper, Thomas Klopstock, Thomas Arzberger, Dieter Edbauer, German Consortium for Frontotemporal Lobar Degeneration, Bavarian Brain Banking Alliance

Published in: Acta Neuropathologica | Issue 4/2015

Abstract

A massive expansion of a GGGGCC repeat upstream of the C9orf72 coding region is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. Despite its intronic localization and lack of a canonical start codon, both strands are translated into aggregating dipeptide repeat (DPR) proteins: poly-GA, poly-GP, poly-GR, poly-PR and poly-PA. To address conflicting findings on the predominant toxicity of the different DPR species in model systems, we compared the expression pattern of the DPR proteins in rat primary neurons and postmortem brain and spinal cord of C9orf72 mutation patients. Only poly-GA overexpression closely mimicked the p62-positive neuronal cytoplasmic inclusions commonly observed for all DPR proteins in patients. In contrast, overexpressed poly-GR and poly-PR formed nucleolar p62-negative inclusions. In patients, most of the less common neuronal intranuclear DPR inclusions were para-nucleolar and p62 positive. Neuronal nucleoli in C9orf72 cases showed normal size and morphology regardless of the presence of poly-GR and poly-PR inclusions arguing against widespread nucleolar stress, reported in cellular models. Colocalization of para-nucleolar DPR inclusions with heterochromatin and a marker of transcriptional repression (H3K9me2) indicates a link to gene transcription. In contrast, we detected numerous intranuclear DPR inclusions not associated with nucleolar structures in ependymal and subependymal cells. In patients, neuronal inclusions of poly-GR, poly-GP and the poly-GA interacting protein Unc119 were less abundant than poly-GA inclusions, but showed similar regional and subcellular distribution. Regardless of neurodegeneration, all inclusions were most abundant in neocortex, hippocampus and thalamus, with few inclusions in brain stem and spinal cord. In the granular cell layer of the cerebellum, poly-GA and Unc119 inclusions were significantly more abundant in cases with FTLD than in cases with MND and FTLD/MND. Poly-PR inclusions were rare throughout the brain but significantly more abundant in the CA3/4 region of FTLD cases than in MND cases. Thus, although DPR distribution is not correlated with neurodegeneration spatially, it correlates with neuropathological subtypes.

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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. doi:10.1016/j.neuron.2013.02.004 PubMedCentralPubMed

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 (2014) 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. doi:10.1111/nan.12178

Beach TG, Walker DG, Sue LI, Newell A, Adler CC, Joyce JN (2004) Substantia nigra Marinesco bodies are associated with decreased striatal expression of dopaminergic markers. J Neuropathol Exp Neurol 63:329–337PubMed

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 126:895–905. doi:10.1007/s00401-013-1199-1 PubMedCentralCrossRefPubMed

Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M, Lee CW, Jansen-West K, Kurti A, Murray ME, Bieniek KF, Bauer PO, Whitelaw EC, Rousseau L, Stankowski JN, Stetler C, Daughrity LM, Perkerson EA, Desaro P, Johnston A, Overstreet K, Edbauer D, Rademakers R, Boylan KB, Dickson DW, Fryer JD, Petrucelli L (2015) C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science. doi:10.1126/science.aaa9344 PubMed

Chi L, Ke Y, Luo C, Li B, Gozal D, Kalyanaraman B, Liu R (2006) Motor neuron degeneration promotes neural progenitor cell proliferation, migration, and neurogenesis in the spinal cords of amyotrophic lateral sclerosis mice. Stem Cells 24:34–43. doi:10.1634/stemcells.2005-0076 PubMedCentralCrossRefPubMed

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 74:180–187. doi:10.1002/ana.23946 PubMed

Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, Pickering-Brown S, Kirby J, Hautbergue GM, Shaw PJ (2015) Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. doi:10.1007/s00401-015-1429-9 PubMedCentralPubMed

Cooper-Knock J, Walsh MJ, Higginbottom A, Robin Highley J, Dickman MJ, Edbauer D, Ince PG, Wharton SB, Wilson SA, Kirby J, Hautbergue GM, Shaw PJ (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137:2040–2051. doi:10.1093/brain/awu120 PubMedCentralCrossRefPubMed

10.

Davidson YS, Barker H, Robinson AC, Thompson JC, Harris J, Troakes C, Smith B, Al-Saraj S, Shaw C, Rollinson S, Masuda-Suzukake M, Hasegawa M, Pickering-Brown S, Snowden JS, Mann DM (2014) Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 2:70. doi:10.1186/2051-5960-2-70 PubMedCentralCrossRefPubMed

11.

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 72:245–256. doi:10.1016/j.neuron.2011.09.011 PubMedCentralCrossRefPubMed

12.

Dodge JC, Treleaven CM, Fidler JA, Hester M, Haidet A, Handy C, Rao M, Eagle A, Matthews JC, Taksir TV, Cheng SH, Shihabuddin LS, Kaspar BK (2010) AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice. Mol Ther 18:2075–2084. doi:10.1038/mt.2010.206 PubMedCentralCrossRefPubMed

13.

Downey LE, Fletcher PD, Golden HL, Mahoney CJ, Agustus JL, Schott JM, Rohrer JD, Beck J, Mead S, Rossor MN, Crutch SJ, Warren JD (2014) Altered body schema processing in frontotemporal dementia with C9ORF72 mutations. J Neurol Neurosurg Psychiatry 85:1016–1023. doi:10.1136/jnnp-2013-306995 PubMedCentralCrossRefPubMed

14.

Downey LE, Mahoney CJ, Rossor MN, Crutch SJ, Warren JD (2012) Impaired self-other differentiation in frontotemporal dementia due to the C9ORF72 expansion. Alzheimers Res Ther 4:42. doi:10.1186/alzrt145 PubMedCentralCrossRefPubMed

15.

Fleck D, van Bebber F, Colombo A, Galante C, Schwenk BM, Rabe L, Hampel H, Novak B, Kremmer E, Tahirovic S, Edbauer D, Lichtenthaler SF, Schmid B, Willem M, Haass C (2013) Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci 33:7856–7869. doi:10.1523/JNEUROSCI.3372-12.2013 CrossRefPubMed

16.

Gendron TF, Belzil VV, Zhang YJ, Petrucelli L (2014) Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol 127:359–376. doi:10.1007/s00401-013-1237-z PubMedCentralCrossRefPubMed

17.

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 126:829–844. doi:10.1007/s00401-013-1192-8 PubMedCentralCrossRefPubMed

18.

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 11:54–65. doi:10.1016/S1474-4422(11)70261-7 CrossRefPubMed

19.

Gross H, Barth S, Palermo RD, Mamiani A, Hennard C, Zimber-Strobl U, West MJ, Kremmer E, Grasser FA (2010) Asymmetric Arginine dimethylation of Epstein-Barr virus nuclear antigen 2 promotes DNA targeting. Virology 397:299–310. doi:10.1016/j.virol.2009.11.023 PubMedCentralCrossRefPubMed

20.

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 507:195–200. doi:10.1038/nature13124 PubMedCentralCrossRefPubMed

21.

Hetman M, Pietrzak M (2012) Emerging roles of the neuronal nucleolus. Trends Neurosci 35:305–314. doi:10.1016/j.tins.2012.01.002 PubMedCentralCrossRefPubMed

22.

Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70:532–540. doi:10.1002/ana.22615 PubMedCentralCrossRefPubMed

23.

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 345:1139–1145. doi:10.1126/science.1254917 PubMedCentralCrossRefPubMed

24.

Lafarga M, Berciano MT, Pena E, Mayo I, Castano JG, Bohmann D, Rodrigues JP, Tavanez JP, Carmo-Fonseca M (2002) Clastosome: a subtype of nuclear body enriched in 19S and 20S proteasomes, ubiquitin, and protein substrates of proteasome. Mol Biol Cell 13:2771–2782. doi:10.1091/mbc.E02-03-0122 PubMedCentralCrossRefPubMed

25.

Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR, Jiang J, Watt AT, Chun S, Katz M, Qiu J, Sun Y, Ling SC, Zhu Q, Polymenidou M, Drenner K, Artates JW, McAlonis-Downes M, Markmiller S, Hutt KR, Pizzo DP, Cady J, Harms MB, Baloh RH, Vandenberg SR, Yeo GW, Fu XD, Bennett CF, Cleveland DW, Ravits J (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci 110:E4530–E4539. doi:10.1073/pnas.1318835110 PubMedCentralCrossRefPubMed

26.

Latonen L, Moore HM, Bai B, Jaamaa S, Laiho M (2011) Proteasome inhibitors induce nucleolar aggregation of proteasome target proteins and polyadenylated RNA by altering ubiquitin availability. Oncogene 30:790–805. doi:10.1038/onc.2010.469 CrossRefPubMed

27.

Lee YB, Chen HJ, Peres JN, Gomez-Deza J, Attig J, Stalekar M, Troakes C, Nishimura AL, Scotter EL, Vance C, Adachi Y, Sardone V, Miller JW, Smith BN, Gallo JM, Ule J, Hirth F, Rogelj B, Houart C, Shaw CE (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep 5:1178–1186. doi:10.1016/j.celrep.2013.10.049 PubMedCentralCrossRefPubMed

28.

Liu EY, Russ J, Wu K, Neal D, Suh E, McNally AG, Irwin DJ, Van Deerlin VM, Lee EB (2014) C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol 128:525–541. doi:10.1007/s00401-014-1286-y CrossRefPubMed

29.

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 126:859–879. doi:10.1007/s00401-013-1181-y CrossRefPubMed

30.

Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, Yeatman T, Warrington EK, Schott JM, Fox NC, Rossor MN, Hardy J, Collinge J, Revesz T, Mead S, Warren JD (2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135:736–750. doi:10.1093/brain/awr361 PubMedCentralCrossRefPubMed

31.

Mahoney CJ, Downey LE, Ridgway GR, Beck J, Clegg S, Blair M, Finnegan S, Leung KK, Yeatman T, Golden H, Mead S, Rohrer JD, Fox NC, Warren JD (2012) Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions. Alzheimers Res Ther 4:41. doi:10.1186/alzrt144 PubMedCentralCrossRefPubMed

32.

Mahoney CJ, Simpson IJ, Nicholas JM, Fletcher PD, Downey LE, Golden HL, Clark CN, Schmitz N, Rohrer JD, Schott JM, Zhang H, Ourselin S, Warren JD, Fox NC (2015) Longitudinal diffusion tensor imaging in frontotemporal dementia. Ann Neurol 77:33–46. doi:10.1002/ana.24296 PubMedCentralCrossRefPubMed

33.

Mann DM (2015) Dipeptide repeat protein toxicity in frontotemporal lobar degeneration and in motor neurone disease associated with expansions in C9ORF72-a cautionary note. Neurobiol Aging 36:1224–1226. doi:10.1016/j.neurobiolaging.2014.10.011 CrossRefPubMed

34.

May S, Hornburg D, Schludi MH, Arzberger T, Rentzsch K, Schwenk BM, Grasser FA, Mori K, Kremmer E, Banzhaf-Strathmann J, Mann M, Meissner F, Edbauer D (2014) C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol 128:485–503. doi:10.1007/s00401-014-1329-4 PubMedCentralCrossRefPubMed

35.

Mizielinska S, Gronke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EM, Partridge L, Isaacs AM (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345:1192–1194. doi:10.1126/science.1256800 CrossRefPubMed

36.

Mori K, Arzberger T, Grasser FA, Gijselinck I, May S, Rentzsch K, Weng SM, Schludi MH, van der Zee J, Cruts M, Van Broeckhoven C, Kremmer E, Kretzschmar HA, Haass C, Edbauer D (2013) Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126:881–893. doi:10.1007/s00401-013-1189-3 CrossRefPubMed

37.

Mori K, Lammich S, Mackenzie IR, Forne I, Zilow S, Kretzschmar H, Edbauer D, Janssens J, Kleinberger G, Cruts M, Herms J, Neumann M, Van Broeckhoven C, Arzberger T, Haass C (2013) hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol. doi:10.1007/s00401-013-1088-7

38.

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. doi:10.1126/science.1232927

39.

Nakagawa T, Feliu-Mojer MI, Wulf P, Lois C, Sheng M, Hoogenraad CC (2006) Generation of lentiviral transgenic rats expressing glutamate receptor interacting protein 1 (GRIP1) in brain, spinal cord and testis. J Neurosci Methods 152:1–9CrossRefPubMed

40.

Odagiri S, Tanji K, Mori F, Kakita A, Takahashi H, Kamitani T, Wakabayashi K (2012) Immunohistochemical analysis of Marinesco bodies, using antibodies against proteins implicated in the ubiquitin-proteasome system, autophagy and aggresome formation. Neuropathology 32:261–266. doi:10.1111/j.1440-1789.2011.01267.x CrossRefPubMed

41.

Pollock C, Huang S (2010) The perinucleolar compartment. Cold Spring Harb Perspect Biol 2:a000679. doi:10.1101/cshperspect.a000679 PubMedCentralCrossRefPubMed

42.

Proudfoot M, Gutowski NJ, Edbauer D, Hilton DA, Stephens M, Rankin J, Mackenzie IR (2014) Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability. Acta Neuropathol 127:451–458. doi:10.1007/s00401-014-1245-7 CrossRefPubMed

43.

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, 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 72:257–268. doi:10.1016/j.neuron.2011.09.010 PubMedCentralCrossRefPubMed

44.

Russ J, Liu EY, Wu K, Neal D, Suh E, Irwin DJ, McMillan CT, Harms MB, Cairns NJ, Wood EM, Xie SX, Elman L, McCluskey L, Grossman M, Van Deerlin VM, Lee EB (2015) Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129:39–52. doi:10.1007/s00401-014-1365-0 PubMedCentralCrossRefPubMed

45.

Shav-Tal Y, Blechman J, Darzacq X, Montagna C, Dye BT, Patton JG, Singer RH, Zipori D (2005) Dynamic sorting of nuclear components into distinct nucleolar caps during transcriptional inhibition. Mol Biol Cell 16:2395–2413. doi:10.1091/mbc.E04-11-0992 PubMedCentralCrossRefPubMed

46.

Skourti-Stathaki K, Kamieniarz-Gdula K, Proudfoot NJ (2014) R-loops induce repressive chromatin marks over mammalian gene terminators. Nature 516:436–439. doi:10.1038/nature13787 PubMedCentralCrossRefPubMed

47.

Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, Johnston A, Overstreet K, Oh SY, Todd PK, Berry JD, Cudkowicz ME, Boeve BF, Dickson D, Floeter MK, Traynor BJ, Morelli C, Ratti A, Silani V, Rademakers R, Brown RH, Rothstein JD, Boylan KB, Petrucelli L, Disney MD (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043–1050. doi:10.1016/j.neuron.2014.07.041 PubMedCentralCrossRefPubMed

48.

Tada T, Simonetta A, Batterton M, Kinoshita M, Edbauer D, Sheng M (2007) Role of Septin cytoskeleton in spine morphogenesis and dendrite development in neurons. Curr Biol 17:1752–1758PubMedCentralCrossRefPubMed

49.

Tan RH, Devenney E, Dobson-Stone C, Kwok JB, Hodges JR, Kiernan MC, Halliday GM, Hornberger M (2014) Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS One 9:e105632. doi:10.1371/journal.pone.0105632 PubMedCentralCrossRefPubMed

50.

Tao Z, Wang H, Xia Q, 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. doi:10.1093/hmg/ddv005 PubMedCentral

51.

Therrien M, Rouleau GA, Dion PA, Parker JA (2013) Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS One 8:e83450. doi:10.1371/journal.pone.0083450 PubMedCentralCrossRefPubMed

52.

van Blitterswijk M, Dejesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, Brown PH, Baker MC, Finch NA, Bauer PO, Serrano G, Beach TG, Josephs KA, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, Boylan KB, Petrucelli L, Dickson DW, Rademakers R (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 12:978–988. doi:10.1016/S1474-4422(13)70210-2 CrossRefPubMed

53.

Walker LC, Diamond MI, Duff KE, Hyman BT (2013) Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol 70:304–310. doi:10.1001/jamaneurol.2013.1453 CrossRefPubMed

54.

Wang J, Haeusler AR, Simko EA (2015) Emerging role of RNA*DNA hybrids in C9orf72-linked neurodegeneration. Cell Cycle 14:526–532. doi:10.1080/15384101.2014.995490 PubMed

55.

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 84:1213–1225. doi:10.1016/j.neuron.2014.12.010 CrossRefPubMed

56.

Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, Rutherford NJ, Baker M, Knopman DS, Wszolek ZK, Parisi JE, Dickson DW, Petersen RC, Rademakers R, Jack CR Jr, Josephs KA (2012) Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 135:794–806. doi:10.1093/brain/aws001 PubMedCentralCrossRefPubMed

57.

Yamakawa M, Ito D, Honda T, Kubo KI, Noda M, Nakajima K, Suzuki N (2014) Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum Mol Genet. doi:10.1093/hmg/ddu576 PubMed

58.

Zhang H, Constantine R, Vorobiev S, Chen Y, Seetharaman J, Huang YJ, Xiao R, Montelione GT, Gerstner CD, Davis MW, Inana G, Whitby FG, Jorgensen EM, Hill CP, Tong L, Baehr W (2011) UNC119 is required for G protein trafficking in sensory neurons. Nat Neurosci 14:874–880. doi:10.1038/nn.2835 PubMedCentralCrossRefPubMed

59.

Zhang YJ, Jansen-West K, Xu YF, Gendron TF, Bieniek KF, Lin WL, Sasaguri H, Caulfield T, Hubbard J, Daughrity L, Chew J, Belzil VV, Prudencio M, Stankowski JN, Castanedes-Casey M, Whitelaw E, Ash PE, DeTure M, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505–524. doi:10.1007/s00401-014-1336-5 PubMedCentralCrossRefPubMed

60.

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 110:E4968–E4977. doi:10.1073/pnas.1315438110 PubMedCentralCrossRefPubMed

Title: Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing
Authors: Martin H. Schludi
Stephanie May
Friedrich A. Grässer
Kristin Rentzsch
Elisabeth Kremmer
Clemens Küpper
Thomas Klopstock
Thomas Arzberger
Dieter Edbauer
German Consortium for Frontotemporal Lobar Degeneration
Bavarian Brain Banking Alliance
Publication date: 01-10-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1450-z

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Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing

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