nach oben

Erschienen in:

01.12.2017 | Original Paper

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis

verfasst von: Shahram Saberi, Jennifer E. Stauffer, Jie Jiang, Sandra Diaz Garcia, Amy E. Taylor, Derek Schulte, Takuya Ohkubo, Cheyenne L. Schloffman, Marcus Maldonado, Michael Baughn, Maria J. Rodriguez, Don Pizzo, Don Cleveland, John Ravits

Erschienen in: Acta Neuropathologica | Ausgabe 3/2018

Einloggen, um Zugang zu erhalten

Abstract

Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. We quantitatively studied and compared DPRs, nuclear pore proteins and C9orf72 protein in clinically related and clinically unrelated regions of the central nervous system, and compared them to phosphorylated TDP-43 (pTDP-43), the hallmark protein of ALS. Of the five DPRs, only poly-GR was significantly abundant in clinically related areas compared to unrelated areas (p < 0.001), and formed dendritic-like aggregates in the motor cortex that co-localized with pTDP-43 (p < 0.0001). While most poly-GR dendritic inclusions were pTDP-43 positive, only 4% of pTDP-43 dendritic inclusions were poly-GR positive. Staining for arginine-containing poly-GR and poly-PR in nuclei of neurons produced signals that were not specific to C9 ALS. We could not detect significant differences of nuclear markers RanGap, Lamin B1, and Importin β1 in C9 ALS, although we observed subtle nuclear changes in ALS, both C9 and non-C9, compared to control. The C9orf72 protein itself was diffusely expressed in cytoplasm of large neurons and glia, and nearly 50% reduced, in both clinically related frontal cortex and unrelated occipital cortex, but not in cerebellum. In summary, sense-encoded poly-GR DPR was unique, and localized to dendrites and pTDP43 in motor regions of C9 ALS CNS. This is consistent with new emerging ideas about TDP-43 functions in dendrites.

Nur mit Berechtigung zugänglich

Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobagyi T, Shaw CE (2011) p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122:691–702. https://doi.org/10.1007/s00401-011-0911-2 CrossRefPubMed

Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SSW, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A et al (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81:536–543. https://doi.org/10.1016/j.neuron.2013.12.018 CrossRefPubMedPubMedCentral

Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW 3rd, Rademakers R et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646. https://doi.org/10.1016/j.neuron.2013.02.004 CrossRefPubMedPubMedCentral

Atanasio A, Decman V, White D, Ramos M, Ikiz B, Lee HC, Siao CJ, Brydges S, LaRosa E, Bai Y et al (2016) C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep 6:23204. https://doi.org/10.1038/srep23204 CrossRefPubMedPubMedCentral

Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R, Feldman H, Hsiung GY, Rutherford N, Laluz V et al (2011) Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry 82:196–203. https://doi.org/10.1136/jnnp.2009.204081 CrossRefPubMed

Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y et al (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74:20–38. https://doi.org/10.1002/ana.23937 CrossRefPubMedPubMedCentral

Burberry A, Suzuki N, Wang JY, Moccia R, Mordes DA, Stewart MH, Suzuki-Uematsu S, Ghosh S, Singh A, Merkle FT et al (2016) Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med 8:347ra93. https://doi.org/10.1126/scitranslmed.aaf6038 CrossRefPubMedPubMedCentral

Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M, Lee CW, Jansen-West K, Kurti A, Murray ME et al (2015) Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science (New York, NY) 348:1151–1154. https://doi.org/10.1126/science.aaa9344 CrossRef

Davidson Y, Robinson AC, Liu X, Wu D, Troakes C, Rollinson S, Masuda-Suzukake M, Suzuki G, Nonaka T, Shi J et al (2016) Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins. Neuropathol Appl Neurobiol 42:242–254. https://doi.org/10.1111/nan.12292 CrossRefPubMed

10.

Davidson YS, Robinson AC, Rollinson S, Pickering-Brown S, Xiao S, Robertson J, Mann DMA (2017) Immunohistochemical detection of C9orf72 protein in frontotemporal lobar degeneration and motor neurone disease: patterns of immunostaining and an evaluation of commercial antibodies. Amyotroph Lateral Scler Frontotemporal Degener 1–10. doi:https://doi.org/10.1080/21678421.2017.1359304

11.

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. https://doi.org/10.1016/j.neuron.2011.09.011 CrossRefPubMedPubMedCentral

12.

Devlin AC, Burr K, Borooah S, Foster JD, Cleary EM, Geti I, Vallier L, Shaw CE, Chandran S, Miles GB (2015) Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nature Commun 6:5999. https://doi.org/10.1038/ncomms6999 CrossRef

13.

Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC et al (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525:129–133. https://doi.org/10.1038/nature14974 CrossRefPubMedPubMedCentral

14.

Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T, Daughrity L, Dunmore JH, Castanedes-Casey M, Chew J et al (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. https://doi.org/10.1007/s00401-013-1192-8 CrossRefPubMedPubMedCentral

15.

Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S et al (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. https://doi.org/10.1016/s1474-4422(11)70261-7 CrossRefPubMed

16.

Gomez-Deza J, Lee YB, Troakes C, Nolan M, Al-Sarraj S, Gallo JM, Shaw CE (2015) Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. Acta Neuropathol Commun 3:38. https://doi.org/10.1186/s40478-015-0218-y CrossRefPubMedPubMedCentral

17.

Ishiguro A, Kimura N, Watanabe Y, Watanabe S, Ishihama A (2016) TDP-43 binds and transports G-quadruplex-containing mRNAs into neurites for local translation. Genes Cells 21:466–481. https://doi.org/10.1111/gtc.12352 CrossRefPubMed

18.

Jiang J, Zhu Q, Gendron TF, Saberi S, McAlonis-Downes M, Seelman A, Stauffer JE, Jafar-Nejad P, Drenner K, Schulte D et al (2016) Gain of toxicity from ALS/FTD-Linked repeat expansions in C9ORF72 Is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 90:535–550. https://doi.org/10.1016/j.neuron.2016.04.006 CrossRefPubMedPubMedCentral

19.

Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G et al (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18:1226–1229. https://doi.org/10.1038/nn.4085 CrossRefPubMedPubMedCentral

20.

King A, Maekawa S, Bodi I, Troakes C, Al-Sarraj S (2011) Ubiquitinated, p62 immunopositive cerebellar cortical neuronal inclusions are evident across the spectrum of TDP-43 proteinopathies but are only rarely additionally immunopositive for phosphorylation-dependent TDP-43. Neuropathology 31:239–249. https://doi.org/10.1111/j.1440-1789.2010.01171.x CrossRefPubMed

21.

Koppers M, Blokhuis AM, Westeneng HJ, Terpstra ML, Zundel CA, Vieira de Sa R, Schellevis RD, Waite AJ, Blake DJ, Veldink JH et al (2015) C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 78:426–438. https://doi.org/10.1002/ana.24453 CrossRefPubMedPubMedCentral

22.

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 (New York, NY) 345:1139–1145. https://doi.org/10.1126/science.1254917 CrossRef

23.

Lall D, Baloh RH (2017) Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. J Clin Investig. https://doi.org/10.1172/jci90607 PubMed

24.

Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, Cika J, Coughlin M, Messing J, Molliex A et al (2016) C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167(774–788):e717. https://doi.org/10.1016/j.cell.2016.10.002

25.

Lee YB, Chen HJ, Peres JN, Gomez-Deza J, Attig J, Stalekar M, Troakes C, Nishimura AL, Scotter EL, Vance C et al (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep 5:1178–1186. https://doi.org/10.1016/j.celrep.2013.10.049 CrossRefPubMedPubMedCentral

26.

Lin Y, Mori E, Kato M, Xiang S, Wu L, Kwon I, McKnight SL (2016) Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell 167(789–802):e712. https://doi.org/10.1016/j.cell.2016.10.003

27.

Liu-Yesucevitz L, Lin AY, Ebata A, Boon JY, Reid W, Xu YF, Kobrin K, Murphy GJ, Petrucelli L, Wolozin B (2014) ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci 34:4167–4174. https://doi.org/10.1523/jneurosci.2350-13.2014 CrossRefPubMedPubMedCentral

28.

Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt DR, Yachnis AT, Ranum LP (2016) C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90:521–534. https://doi.org/10.1016/j.neuron.2016.04.005 CrossRefPubMed

29.

Lopez-Gonzalez R, Lu Y, Gendron TF, Karydas A, Tran H, Yang D, Petrucelli L, Miller BL, Almeida S, Gao FB (2016) Poly(GR) in C9ORF72-Related ALS/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons. Neuron 92:383–391. https://doi.org/10.1016/j.neuron.2016.09.015 CrossRefPubMedPubMedCentral

30.

Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K, Weng SM, Haass C, Kretzschmar HA, Edbauer D et al (2013) Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 126:859–879. https://doi.org/10.1007/s00401-013-1181-y CrossRefPubMed

31.

Mackenzie IR, Frick P, Grasser FA, Gendron TF, Petrucelli L, Cashman NR, Edbauer D, Kremmer E, Prudlo J, Troost D et al (2015) Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol 130:845–861. https://doi.org/10.1007/s00401-015-1476-2 CrossRefPubMed

32.

Mann DM, Rollinson S, Robinson A, Bennion Callister J, Thompson JC, Snowden JS, Gendron T, Petrucelli L, Masuda-Suzukake M, Hasegawa M et al (2013) Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 1:68. https://doi.org/10.1186/2051-5960-1-68 CrossRefPubMedPubMedCentral

33.

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

34.

Mizielinska S, Gronke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J et al (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science (New York, NY) 345:1192–1194. https://doi.org/10.1126/science.1256800 CrossRef

35.

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

36.

Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science (New York, NY) 339:1335–1338. https://doi.org/10.1126/science.1232927 CrossRef

37.

Nishihira Y, Tan CF, Onodera O, Toyoshima Y, Yamada M, Morita T, Nishizawa M, Kakita A, Takahashi H (2008) Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 116:169–182. https://doi.org/10.1007/s00401-008-0385-z CrossRefPubMed

38.

O’Rourke JG, Bogdanik L, Muhammad AK, Gendron TF, Kim KJ, Austin A, Cady J, Liu EY, Zarrow J, Grant S et al (2015) C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88:892–901. https://doi.org/10.1016/j.neuron.2015.10.027 CrossRefPubMedPubMedCentral

39.

O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK, Ho R, Carmona S, Vit JP, Zarrow J et al (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science (New York, NY) 351:1324–1329. https://doi.org/10.1126/science.aaf1064 CrossRef

40.

Peters OM, Cabrera GT, Tran H, Gendron TF, McKeon JE, Metterville J, Weiss A, Wightman N, Salameh J, Kim J et al (2015) Human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice. Neuron 88:902–909. https://doi.org/10.1016/j.neuron.2015.11.018 CrossRefPubMedPubMedCentral

41.

Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. https://doi.org/10.1016/j.neuron.2011.09.010 CrossRefPubMedPubMedCentral

42.

Rossi S, Serrano A, Gerbino V, Giorgi A, Di Francesco L, Nencini M, Bozzo F, Schinina ME, Bagni C, Cestra G et al (2015) Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. J Cell Sci 128:1787–1799. https://doi.org/10.1242/jcs.165332 CrossRefPubMed

43.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019 CrossRefPubMed

44.

Schludi MH, Becker L, Garrett L, Gendron TF, Zhou Q, Schreiber F, Popper B, Dimou L, Strom TM, Winkelmann J et al (2017) Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss. Acta Neuropathol. https://doi.org/10.1007/s00401-017-1711-0 PubMedPubMedCentral

45.

Schludi MH, May S, Grasser FA, Rentzsch K, Kremmer E, Kupper C, Klopstock T, Arzberger T, German Consortium for Frontotemporal Lobar D, Bavarian Brain Banking A et al (2015) Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol 130:537–555. https://doi.org/10.1007/s00401-015-1450-z CrossRefPubMedPubMedCentral

46.

Schwenk BM, Hartmann H, Serdaroglu A, Schludi MH, Hornburg D, Meissner F, Orozco D, Colombo A, Tahirovic S, Michaelsen M et al (2016) TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. EMBO J 35:2350–2370. https://doi.org/10.15252/embj.201694221 CrossRefPubMedPubMedCentral

47.

Sudria-Lopez E, Koppers M, de Wit M, van der Meer C, Westeneng HJ, Zundel CA, Youssef SA, Harkema L, de Bruin A, Veldink JH et al (2016) Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects. Acta Neuropathol 132:145–147. https://doi.org/10.1007/s00401-016-1581-x CrossRefPubMedPubMedCentral

48.

Takeuchi R, Tada M, Shiga A, Toyoshima Y, Konno T, Sato T, Nozaki H, Kato T, Horie M, Shimizu H et al (2016) Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: evidence for clinico-pathologic subtypes. Acta Neuropathol Commun 4:61. https://doi.org/10.1186/s40478-016-0335-2 CrossRefPubMedPubMedCentral

49.

Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z et al (2015) Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a drosophila model of C9ORF72 FTD/ALS. Neuron 87:1207–1214. https://doi.org/10.1016/j.neuron.2015.09.015 CrossRefPubMedPubMedCentral

50.

van Blitterswijk M, Gendron TF, Baker MC, DeJesus-Hernandez M, Finch NA, Brown PH, Daughrity LM, Murray ME, Heckman MG, Jiang J et al (2015) Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72. Acta Neuropathol 130:863–876. https://doi.org/10.1007/s00401-015-1480-6 CrossRefPubMedPubMedCentral

51.

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(7):1779.e5–1779.e13. https://doi.org/10.1016/j.neurobiolaging.2014.01.016 CrossRef

52.

Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y, Lin S, Shneider NA, Monaghan J, Pandey UB 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. https://doi.org/10.1016/j.neuron.2014.12.010 CrossRefPubMedPubMedCentral

53.

Xiao S, MacNair L, McGoldrick P, McKeever PM, McLean JR, Zhang M, Keith J, Zinman L, Rogaeva E, Robertson J (2015) Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol 78:568–583. https://doi.org/10.1002/ana.24469 CrossRefPubMed

54.

Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS et al (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci USA 110:7778–7783. https://doi.org/10.1073/pnas.1219643110 CrossRefPubMedPubMedCentral

55.

Yang D, Abdallah A, Li Z, Lu Y, Almeida S, Gao FB (2015) FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol 130:525–535. https://doi.org/10.1007/s00401-015-1448-6 CrossRefPubMedPubMedCentral

56.

Yin S, Lopez-Gonzalez R, Kunz RC, Gangopadhyay J, Borufka C, Gygi SP, Gao FB, Reed R (2017) Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients. Cell Rep 19:2244–2256. https://doi.org/10.1016/j.celrep.2017.05.056 CrossRefPubMedPubMedCentral

57.

Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S et al (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56–61. https://doi.org/10.1038/nature14973 CrossRefPubMedPubMedCentral

58.

Zhang YJ, Gendron TF, Grima JC, Sasaguri H, Jansen-West K, Xu YF, Katzman RB, Gass J, Murray ME, Shinohara M et al (2016) C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci 19:668–677. https://doi.org/10.1038/nn.4272 CrossRefPubMedPubMedCentral

59.

Zhang YJ, Jansen-West K, Xu YF, Gendron TF, Bieniek KF, Lin WL, Sasaguri H, Caulfield T, Hubbard J, Daughrity L et al (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505–524. https://doi.org/10.1007/s00401-014-1336-5 CrossRefPubMedPubMedCentral

60.

Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH et al (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci USA 110:E4968–4977. https://doi.org/10.1073/pnas.1315438110 CrossRefPubMedPubMedCentral

Titel: Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis
verfasst von: Shahram Saberi
Jennifer E. Stauffer
Jie Jiang
Sandra Diaz Garcia
Amy E. Taylor
Derek Schulte
Takuya Ohkubo
Cheyenne L. Schloffman
Marcus Maldonado
Michael Baughn
Maria J. Rodriguez
Don Pizzo
Don Cleveland
John Ravits
Publikationsdatum: 01.12.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 3/2018
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1793-8

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Schützt Olivenöl vor dem Tod durch Demenz?

10.05.2024 Morbus Alzheimer Nachrichten

Konsumieren Menschen täglich 7 Gramm Olivenöl, ist ihr Risiko, an einer Demenz zu sterben, um mehr als ein Vierten reduziert – und dies weitgehend unabhängig von ihrer sonstigen Ernährung. Dafür sprechen Auswertungen zweier großer US-Studien.

Bluttest erkennt Parkinson schon zehn Jahre vor der Diagnose

10.05.2024 Parkinson-Krankheit Nachrichten

Ein Bluttest kann abnorm aggregiertes Alpha-Synuclein bei einigen Menschen schon zehn Jahre vor Beginn der motorischen Parkinsonsymptome nachweisen. Mit einem solchen Test lassen sich möglicherweise Prodromalstadien erfassen und die Betroffenen früher behandeln.

Darf man die Behandlung eines Neonazis ablehnen?

08.05.2024 Gesellschaft Nachrichten

In einer Leseranfrage in der Zeitschrift Journal of the American Academy of Dermatology möchte ein anonymer Dermatologe bzw. eine anonyme Dermatologin wissen, ob er oder sie einen Patienten behandeln muss, der eine rassistische Tätowierung trägt.

Wartezeit nicht kürzer, aber Arbeit flexibler

Psychotherapie Medizin aktuell

Fünf Jahren nach der Neugestaltung der Psychotherapie-Richtlinie wurden jetzt die Effekte der vorgenommenen Änderungen ausgewertet. Das Hauptziel der Novellierung war eine kürzere Wartezeit auf Therapieplätze. Dieses Ziel wurde nicht erreicht, es gab jedoch positive Auswirkungen auf andere Bereiche.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Klimawandel und Gesundheit: Was Sie in der Hausarztpraxis wissen müssen und tun können

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2018

Functional morphology of the blood–brain barrier in health and disease

Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

Cluster: barriers of the central nervous system

cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC)