Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition

EMBO Reports

Volumn 17, Issue 9, 2016, Pages 1314-1325

  Mori, Kohji ^a,i   Nihei, Yoshihiro ^a   Arzberger, Thomas ^a,b,c   Zhou, Qihui ^b   Mackenzie, Ian R ^d   Hermann, Andreas ^b,e   Hanisch, Frank ^f,g   Kamp, Frits ^a   Nuscher, Brigitte ^a   Orozco, Denise ^b   Edbauer, Dieter ^b,h   Haass, Christian ^a,b,h  

^a UNIVERSITY OF MUNICH   (Germany)

^b GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^c LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^d UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^e CENTER FOR REGENERATIVE THERAPIES DRESDEN   (Germany)

^f MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

^g VIVANTES HOSPITAL   (Germany)

^h Germany 3 Munich Cluster for Systems Neurology   (Germany)

ⁱ OSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

C9orf72; dipeptide repeat proteins; frontotemporal lobar degeneration; hnRNPA3; neurodegeneration

Indexed keywords

DIPEPTIDE; DIPEPTIDE REPEAT PROTEIN; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN HNRNPA1; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN HNRNPA2; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN HNRNPA3; NUCLEAR RNA; RNA; UNCLASSIFIED DRUG;

ADULT; ANIMAL CELL; ARTICLE; C9ORF72 REPEAT GENE; CONTROLLED STUDY; EMBRYO; FEMALE; GENE; GENE EXPRESSION; GENE REPRESSION; HELA CELL LINE; HIPPOCAMPUS; HUMAN; HUMAN CELL; HUMAN TISSUE; MALE; MIDDLE AGED; NERVE CELL; NEUROPATHOLOGY; NONHUMAN; NUCLEAR IMPORT; NUCLEAR LOCALIZATION SIGNAL; NUCLEOTIDE REPEAT; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN TRANSPORT; RAT; TISSUE CULTURE;

EID: 84985028167     PISSN: 1469221X     EISSN: 14693178     Source Type: Journal    
DOI: 10.15252/embr.201541724     Document Type: Article

References (25)

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 et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77: 639–646
2. 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
3. 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
4. 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 339: 1335–1338
5. 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 U S A 110: E4968–E4977
6. Mori K, Lammich S, Mackenzie IR, Forne I, Zilow S, Kretzschmar H, Edbauer D, Janssens J, Kleinberger G, Cruts M et al (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 125: 413–423
7. Donnelly CJ, Zhang PW, Pham JT, Heusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM et al (2013) RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention. Neuron 80: 415–428
8. 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
9. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495: 467–473
10. Mayeda A, Munroe SH, Caceres JF, Krainer AR (1994) Function of conserved domains of hnRNP A1 and other hnRNP A/B proteins. EMBO J 13: 5483–5495
11. 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
12. 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
13. 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
14. Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R et al (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507: 195–200
15. 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 345: 1192–1194
16. 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
17. 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
18. 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) C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348: 1151–1154
19. 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
20. 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
21. Orozco D, Tahirovic S, Rentzsch K, Schwenk BM, Haass C, Edbauer D (2012) Loss of fused in sarcoma (FUS) promotes pathological Tau splicing. EMBO Rep 13: 759–764
22. 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
23. Mizielinska S, Lashley T, Norona FE, Clayton EL, Ridler CE, Fratta P, Isaacs AM (2013) C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol 126: 845–857
24. Schludi MH, May S, Grasser FA, Rentzsch K, Kremmer E, Kupper C, Klopstock T, German Consortium for Frontotemporal Lobar Degeneration, Bavarian Brain Banking Alliance, Arzberger T 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
25. 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