{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T12:11:18Z","timestamp":1777464678488,"version":"3.51.4"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T00:00:00Z","timestamp":1571788800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T00:00:00Z","timestamp":1571788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008483","name":"NOMIS Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008483","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Munich Cluster of Systems Neurology"},{"name":"Helmholtz Virtual Institute","award":["VH-VI-510"],"award-info":[{"award-number":["VH-VI-510"]}]},{"name":"Helmholtz Virtual Institute","award":["VH-VI-510"],"award-info":[{"award-number":["VH-VI-510"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP16H05379"],"award-info":[{"award-number":["JP16H05379"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP17H05091"],"award-info":[{"award-number":["JP17H05091"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP18K19515"],"award-info":[{"award-number":["JP18K19515"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP18ek0109316"],"award-info":[{"award-number":["JP18ek0109316"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005865","name":"Mochida Memorial Foundation for Medical and Pharmaceutical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008667","name":"SENSHIN Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008667","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hermann und Lilly Schilling-Stiftung f\u00fcr medizinische Forschung im Stifterverband"},{"DOI":"10.13039\/501100004963","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["617198"],"award-info":[{"award-number":["617198"]}],"id":[{"id":"10.13039\/501100004963","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Swiss ALS Foundation","award":["None"],"award-info":[{"award-number":["None"]}]},{"name":"the Swiss ALS Foundation","award":["None"],"award-info":[{"award-number":["None"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:p>Repeat expansion in <jats:italic>C9orf72<\/jats:italic> causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in <jats:italic>C9orf72<\/jats:italic> are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in <jats:italic>C9orf72<\/jats:italic> patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine\u2013arginine and poly-proline-arginine increased foci formed by phosphorylated\u00a0Ataxia Telangiectasia Mutated\u00a0(pATM), a major sensor of DSBs, whereas poly-glycine\u2013alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of <jats:italic>C9orf72<\/jats:italic> patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in <jats:italic>C9orf72<\/jats:italic> patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB.<\/jats:p>","DOI":"10.1007\/s00401-019-02082-0","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T16:02:10Z","timestamp":1571846530000},"page":"99-118","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Poly-glycine\u2013alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3"],"prefix":"10.1007","volume":"139","author":[{"name":"German Consortium for Frontotemporal Lobar Degeneration","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Nihei","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Bavarian Brain Banking Alliance","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohji","family":"Mori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Werner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Arzberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qihui","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barham","family":"Khosravi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Japtok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Sommacal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Weber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frits","family":"Kamp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte","family":"Nuscher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Edbauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Haass","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,10,23]]},"reference":[{"key":"2082_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.compbiolchem.2004.11.002","volume":"29","author":"AA Akindahunsi","year":"2005","unstructured":"Akindahunsi AA, Bandiera A, Manzini G (2005) Vertebrate 2xRBD hnRNP proteins: a comparative analysis of genome, mRNA and protein sequences. Comput Biol Chem 29:13\u201323. \nhttps:\/\/doi.org\/10.1016\/j.compbiolchem.2004.11.002","journal-title":"Comput Biol Chem"},{"key":"2082_CR2","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.neuron.2013.02.004","volume":"77","author":"PE Ash","year":"2013","unstructured":"Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD\/ALS. Neuron 77:639\u2013646. \nhttps:\/\/doi.org\/10.1016\/j.neuron.2013.02.004","journal-title":"Neuron"},{"key":"2082_CR3","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nature01368","volume":"421","author":"CJ Bakkenist","year":"2003","unstructured":"Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499\u2013506. \nhttps:\/\/doi.org\/10.1038\/nature01368","journal-title":"Nature"},{"key":"2082_CR4","doi-asserted-by":"publisher","first-page":"33826","DOI":"10.1074\/jbc.M502477200","volume":"280","author":"S Barker","year":"2005","unstructured":"Barker S, Weinfeld M, Zheng J, Li L, Murray D (2005) Identification of mammalian proteins cross-linked to DNA by ionizing radiation. J Biol Chem 280:33826\u201333838. \nhttps:\/\/doi.org\/10.1074\/jbc.M502477200","journal-title":"J Biol Chem"},{"key":"2082_CR5","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1038\/cdd.2016.23","volume":"23","author":"J Barroso-Gonzalez","year":"2016","unstructured":"Barroso-Gonzalez J, Auclair S, Luan S, Thomas L, Atkins KM, Aslan JE et al (2016) PACS-2 mediates the ATM and NF-kappaB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage. Cell Death Differ 23:1448\u20131457. \nhttps:\/\/doi.org\/10.1038\/cdd.2016.23","journal-title":"Cell Death Differ"},{"key":"2082_CR6","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1038\/ng1769","volume":"38","author":"A Bender","year":"2006","unstructured":"Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH et al (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515\u2013517. \nhttps:\/\/doi.org\/10.1038\/ng1769","journal-title":"Nat Genet"},{"key":"2082_CR7","doi-asserted-by":"publisher","first-page":"5069","DOI":"10.1093\/hmg\/ddw327","volume":"25","author":"J Bennion Callister","year":"2016","unstructured":"Bennion Callister J, Ryan S, Sim J, Rollinson S, Pickering-Brown SM (2016) Modelling C9orf72 dipeptide repeat proteins of a physiologically relevant size. Hum Mol Genet 25:5069\u20135082. \nhttps:\/\/doi.org\/10.1093\/hmg\/ddw327","journal-title":"Hum Mol Genet"},{"key":"2082_CR8","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.molcel.2018.08.032","volume":"71","author":"S Boeynaems","year":"2018","unstructured":"Boeynaems S, Gitler AD (2018) Pour Some Sugar on TDP(-43). Mol Cell 71:649\u2013651. \nhttps:\/\/doi.org\/10.1016\/j.molcel.2018.08.032","journal-title":"Mol Cell"},{"key":"2082_CR9","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1111\/jnc.12444","volume":"128","author":"MA Bradley-Whitman","year":"2014","unstructured":"Bradley-Whitman MA, Timmons MD, Beckett TL, Murphy MP, Lynn BC, Lovell MA (2014) Nucleic acid oxidation: an early feature of Alzheimer's disease. J Neurochem 128:294\u2013304. \nhttps:\/\/doi.org\/10.1111\/jnc.12444","journal-title":"J Neurochem"},{"key":"2082_CR10","doi-asserted-by":"publisher","first-page":"42462","DOI":"10.1074\/jbc.C100466200","volume":"276","author":"S Burma","year":"2001","unstructured":"Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276:42462\u201342467. \nhttps:\/\/doi.org\/10.1074\/jbc.C100466200","journal-title":"J Biol Chem"},{"key":"2082_CR11","doi-asserted-by":"publisher","first-page":"3865","DOI":"10.1007\/s00018-010-0408-5","volume":"67","author":"A Camins","year":"2010","unstructured":"Camins A, Pizarro JG, Alvira D, Gutierrez-Cuesta J, de la Torre AV, Folch J et al (2010) Activation of ataxia telangiectasia muted under experimental models and human Parkinson's disease. Cell Mol Life Sci 67:3865\u20133882. \nhttps:\/\/doi.org\/10.1007\/s00018-010-0408-5","journal-title":"Cell Mol Life Sci"},{"key":"2082_CR12","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.1038\/s41598-018-20360-x","volume":"8","author":"A Cloutier","year":"2018","unstructured":"Cloutier A, Shkreta L, Toutant J, Durand M, Thibault P, Chabot B (2018) hnRNP A1\/A2 and Sam68 collaborate with SRSF10 to control the alternative splicing response to oxaliplatin-mediated DNA damage. Sci Rep 8:2206. \nhttps:\/\/doi.org\/10.1038\/s41598-018-20360-x","journal-title":"Sci Rep"},{"key":"2082_CR13","doi-asserted-by":"publisher","first-page":"3720","DOI":"10.1096\/fj.13-239129","volume":"28","author":"M Comegna","year":"2014","unstructured":"Comegna M, Succoio M, Napolitano M, Vitale M, D'Ambrosio C, Scaloni A et al (2014) Identification of miR-494 direct targets involved in senescence of human diploid fibroblasts. FASEB J 28:3720\u20133733. \nhttps:\/\/doi.org\/10.1096\/fj.13-239129","journal-title":"FASEB J"},{"key":"2082_CR14","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","volume":"72","author":"M DeJesus-Hernandez","year":"2011","unstructured":"DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245\u2013256. \nhttps:\/\/doi.org\/10.1016\/j.neuron.2011.09.011","journal-title":"Neuron"},{"key":"2082_CR15","doi-asserted-by":"publisher","first-page":"2882","DOI":"10.1093\/hmg\/ddx170","volume":"26","author":"MA Farg","year":"2017","unstructured":"Farg MA, Konopka A, Ying Soo K, 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\u20132896. \nhttps:\/\/doi.org\/10.1093\/hmg\/ddx170","journal-title":"Hum Mol Genet"},{"key":"2082_CR16","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1007\/s12035-013-8591-7","volume":"49","author":"ML Ferlazzo","year":"2014","unstructured":"Ferlazzo ML, Sonzogni L, Granzotto A, Bodgi L, Lartin O, Devic C et al (2014) Mutations of the Huntington's disease protein impact on the ATM-dependent signaling and repair pathways of the radiation-induced DNA double-strand breaks: corrective effect of statins and bisphosphonates. Mol Neurobiol 49:1200\u20131211. \nhttps:\/\/doi.org\/10.1007\/s12035-013-8591-7","journal-title":"Mol Neurobiol"},{"key":"2082_CR17","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1159\/000481258","volume":"17","author":"JA Fifita","year":"2017","unstructured":"Fifita JA, Zhang KY, Galper J, Williams KL, McCann EP, Hogan AL et al (2017) Genetic and pathological assessment of hnRNPA1, hnRNPA2\/B1, and hnRNPA3 in familial and sporadic amyotrophic lateral sclerosis. Neurodegener Dis 17:304\u2013312. \nhttps:\/\/doi.org\/10.1159\/000481258","journal-title":"Neurodegener Dis"},{"key":"2082_CR18","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1038\/srep01016","volume":"2","author":"P Fratta","year":"2012","unstructured":"Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EM, Parkinson G et al (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2:1016. \nhttps:\/\/doi.org\/10.1038\/srep01016","journal-title":"Sci Rep"},{"key":"2082_CR19","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1038\/nature14974","volume":"525","author":"BD Freibaum","year":"2015","unstructured":"Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH et al (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525:129\u2013133. \nhttps:\/\/doi.org\/10.1038\/nature14974","journal-title":"Nature"},{"key":"2082_CR20","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/s1474-4422(11)70261-7","volume":"11","author":"I Gijselinck","year":"2012","unstructured":"Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G 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\u201365. \nhttps:\/\/doi.org\/10.1016\/s1474-4422(11)70261-7","journal-title":"Lancet Neurol"},{"key":"2082_CR21","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1093\/hmg\/ddg242","volume":"12","author":"P Giuliano","year":"2003","unstructured":"Giuliano P, De Cristofaro T, Affaitati A, Pizzulo GM, Feliciello A, Criscuolo C et al (2003) DNA damage induced by polyglutamine-expanded proteins. Hum Mol Genet 12:2301\u20132309. \nhttps:\/\/doi.org\/10.1093\/hmg\/ddg242","journal-title":"Hum Mol Genet"},{"key":"2082_CR22","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.mcn.2018.08.002","volume":"92","author":"H Glass","year":"2018","unstructured":"Glass H, Pal A, Reinhardt P, Sterneckert J, Wegner F, Storch A et al (2018) Defective mitochondrial and lysosomal trafficking in chorea-acanthocytosis is independent of Src-kinase signaling. Mol Cell Neurosci 92:137\u2013148. \nhttps:\/\/doi.org\/10.1016\/j.mcn.2018.08.002","journal-title":"Mol Cell Neurosci"},{"key":"2082_CR23","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nature13124","volume":"507","author":"AR Haeusler","year":"2014","unstructured":"Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS et al (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507:195\u2013200. \nhttps:\/\/doi.org\/10.1038\/nature13124","journal-title":"Nature"},{"key":"2082_CR24","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1080\/09553000903009548","volume":"85","author":"B Haley","year":"2009","unstructured":"Haley B, Paunesku T, Protic M, Woloschak GE (2009) Response of heterogeneous ribonuclear proteins (hnRNP) to ionising radiation and their involvement in DNA damage repair. Int J Radiat Biol 85:643\u2013655. \nhttps:\/\/doi.org\/10.1080\/09553000903009548","journal-title":"Int J Radiat Biol"},{"key":"2082_CR25","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1212\/WNL.45.10.1879","volume":"45","author":"TM Horton","year":"1995","unstructured":"Horton TM, Graham BH, Corral-Debrinski M, Shoffner JM, Kaufman AE, Beal MF et al (1995) Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients. Neurology 45:1879\u20131883","journal-title":"Neurology"},{"key":"2082_CR26","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/j.nbd.2015.07.017","volume":"82","author":"J Japtok","year":"2015","unstructured":"Japtok J, Lojewski X, Naumann M, Klingenstein M, Reinhardt P, Sterneckert J et al (2015) Stepwise acquirement of hallmark neuropathology in FUS-ALS iPSC models depends on mutation type and neuronal aging. Neurobiol Dis 82:420\u2013429. \nhttps:\/\/doi.org\/10.1016\/j.nbd.2015.07.017","journal-title":"Neurobiol Dis"},{"key":"2082_CR27","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw052","author":"K Kanekura","year":"2016","unstructured":"Kanekura K, Yagi T, Cammack AJ, Mahadevan J, Kuroda M, Harms MB et al (2016) Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. Hum Mol Genet. \nhttps:\/\/doi.org\/10.1093\/hmg\/ddw052","journal-title":"Hum Mol Genet"},{"key":"2082_CR28","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1093\/hmg\/ddw432","volume":"26","author":"B Khosravi","year":"2017","unstructured":"Khosravi B, Hartmann H, May S, Mohl C, Ederle H, Michaelsen M et al (2017) Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS\/FTLD. Hum Mol Genet 26:790\u2013800. \nhttps:\/\/doi.org\/10.1093\/hmg\/ddw432","journal-title":"Hum Mol Genet"},{"key":"2082_CR29","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1126\/science.1254917","volume":"345","author":"I Kwon","year":"2014","unstructured":"Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T et al (2014) Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345:1139\u20131145. \nhttps:\/\/doi.org\/10.1126\/science.1254917","journal-title":"Science"},{"key":"2082_CR30","doi-asserted-by":"publisher","first-page":"3295","DOI":"10.1242\/dev.01179","volume":"131","author":"SK Lee","year":"2004","unstructured":"Lee SK, Jurata LW, Funahashi J, Ruiz EC, Pfaff SL (2004) Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with enhancer factors. Development 131:3295\u20133306. \nhttps:\/\/doi.org\/10.1242\/dev.01179","journal-title":"Development"},{"key":"2082_CR31","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1093\/hmg\/ddg218","volume":"12","author":"H Li","year":"2003","unstructured":"Li H, Wyman T, Yu ZX, Li SH, Li XJ (2003) Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release. Hum Mol Genet 12:2021\u20132030. \nhttps:\/\/doi.org\/10.1093\/hmg\/ddg218","journal-title":"Hum Mol Genet"},{"key":"2082_CR32","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.neuron.2016.09.015","volume":"92","author":"R Lopez-Gonzalez","year":"2016","unstructured":"Lopez-Gonzalez R, Lu Y, Gendron TF, Karydas A, Tran H, Yang D et al (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\u2013391. \nhttps:\/\/doi.org\/10.1016\/j.neuron.2016.09.015","journal-title":"Neuron"},{"issue":"490\u2013504","key":"2082_CR33","doi-asserted-by":"publisher","first-page":"e496","DOI":"10.1016\/j.molcel.2018.11.012","volume":"73","author":"FE Loughlin","year":"2019","unstructured":"Loughlin FE, Lukavsky PJ, Kazeeva T, Reber S, Hock EM, Colombo M et al (2019) The solution structure of FUS bound to RNA reveals a bipartite mode of RNA recognition with both sequence and shape specificity. Mol Cell 73(490\u2013504):e496. \nhttps:\/\/doi.org\/10.1016\/j.molcel.2018.11.012","journal-title":"Mol Cell"},{"key":"2082_CR34","doi-asserted-by":"publisher","first-page":"7497","DOI":"10.1093\/nar\/gkm821","volume":"35","author":"MA Lovell","year":"2007","unstructured":"Lovell MA, Markesbery WR (2007) Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease. Nucleic Acids Res 35:7497\u20137504. \nhttps:\/\/doi.org\/10.1093\/nar\/gkm821","journal-title":"Nucleic Acids Res"},{"key":"2082_CR35","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1007\/s00401-013-1181-y","volume":"126","author":"IR Mackenzie","year":"2013","unstructured":"Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K et al (2013) Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 126:859\u2013879. \nhttps:\/\/doi.org\/10.1007\/s00401-013-1181-y","journal-title":"Acta Neuropathol"},{"issue":"703\u2013717","key":"2082_CR36","doi-asserted-by":"publisher","first-page":"e709","DOI":"10.1016\/j.molcel.2018.07.002","volume":"71","author":"L McGurk","year":"2018","unstructured":"McGurk L, Gomes E, Guo L, Mojsilovic-Petrovic J, Tran V, Kalb RG et al (2018) Poly(ADP-ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol Cell 71(703\u2013717):e709. \nhttps:\/\/doi.org\/10.1016\/j.molcel.2018.07.002","journal-title":"Mol Cell"},{"key":"2082_CR37","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.2174\/15672050136661604011","volume":"13","author":"D Merlo","year":"2016","unstructured":"Merlo D, Mollinari C, Racaniello M, Garaci E, Cardinale A (2016) DNA double strand breaks: a common theme in neurodegenerative diseases. Curr Alzheimer Res 13:1208\u20131218. \nhttps:\/\/doi.org\/10.2174\/15672050136661604011","journal-title":"Curr Alzheimer Res"},{"key":"2082_CR38","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s40478-017-0432-x","volume":"5","author":"S Mizielinska","year":"2017","unstructured":"Mizielinska S, Ridler CE, Balendra R, Thoeng A, Woodling NS, Grasser FA et al (2017) Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathol Commun 5:29. \nhttps:\/\/doi.org\/10.1186\/s40478-017-0432-x","journal-title":"Acta Neuropathol Commun"},{"key":"2082_CR39","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1007\/s00401-013-1200-z","volume":"126","author":"SL Mizielinska","year":"2013","unstructured":"Mizielinska SL, 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\u2013857. \nhttps:\/\/doi.org\/10.1007\/s00401-013-1200-z","journal-title":"Acta Neuropathol"},{"key":"2082_CR40","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1007\/s00401-013-1189-3","volume":"126","author":"K Mori","year":"2013","unstructured":"Mori K, Arzberger T, Grasser FA, Gijselinck I, May S, Rentzsch K et al (2013) Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126:881\u2013893. \nhttps:\/\/doi.org\/10.1007\/s00401-013-1189-3","journal-title":"Acta Neuropathol"},{"key":"2082_CR41","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1007\/s00401-013-1088-7","volume":"125","author":"K Mori","year":"2013","unstructured":"Mori K, Lammich S, Mackenzie IR, Forne I, Zilow S, Kretzschmar H 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\u2013423. \nhttps:\/\/doi.org\/10.1007\/s00401-013-1088-7","journal-title":"Acta Neuropathol"},{"key":"2082_CR42","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.15252\/embr.201541724","volume":"17","author":"K Mori","year":"2016","unstructured":"Mori K, Nihei Y, Arzberger T, Zhou Q, Mackenzie IR, Hermann A et al (2016) Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition. EMBO Rep 17:1314\u20131325. \nhttps:\/\/doi.org\/10.15252\/embr.201541724","journal-title":"EMBO Rep"},{"key":"2082_CR43","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1126\/science.1232927","volume":"339","author":"K Mori","year":"2013","unstructured":"Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD\/ALS. Science 339:1335\u20131338. \nhttps:\/\/doi.org\/10.1126\/science.1232927","journal-title":"Science"},{"key":"2082_CR44","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/s41467-017-02299-1","volume":"9","author":"M Naumann","year":"2018","unstructured":"Naumann M, Pal A, Goswami A, Lojewski X, Japtok J, Vehlow A et al (2018) Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation. Nat Commun 9:335. \nhttps:\/\/doi.org\/10.1038\/s41467-017-02299-1","journal-title":"Nat Commun"},{"key":"2082_CR45","doi-asserted-by":"publisher","first-page":"8043","DOI":"10.1074\/jbc.M112.408211","volume":"288","author":"Y Nihei","year":"2013","unstructured":"Nihei Y, Ito D, Okada Y, Akamatsu W, Yagi T, Yoshizaki T et al (2013) Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy. J Biol Chem 288:8043\u20138052. \nhttps:\/\/doi.org\/10.1074\/jbc.M112.408211","journal-title":"J Biol Chem"},{"key":"2082_CR46","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1080\/21678421.2016.1262423","volume":"18","author":"A Nordin","year":"2017","unstructured":"Nordin A, Akimoto C, Wuolikainen A, Alstermark H, Forsberg K, Baumann P et al (2017) Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study. Amyotroph Lateral Scler Frontotemporal Degener 18:256\u2013264. \nhttps:\/\/doi.org\/10.1080\/21678421.2016.1262423","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2082_CR47","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/nrg1746","volume":"7","author":"M O'Driscoll","year":"2006","unstructured":"O'Driscoll M, Jeggo PA (2006) The role of double-strand break repair - insights from human genetics. Nat Rev Genet 7:45\u201354. \nhttps:\/\/doi.org\/10.1038\/nrg1746","journal-title":"Nat Rev Genet"},{"key":"2082_CR48","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/j.cell.2015.07.047","volume":"162","author":"A Patel","year":"2015","unstructured":"Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY et al (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066\u20131077. \nhttps:\/\/doi.org\/10.1016\/j.cell.2015.07.047","journal-title":"Cell"},{"key":"2082_CR49","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1038\/nprot.2013.143","volume":"8","author":"FA Ran","year":"2013","unstructured":"Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281\u20132308. \nhttps:\/\/doi.org\/10.1038\/nprot.2013.143","journal-title":"Nat Protoc"},{"key":"2082_CR50","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","volume":"72","author":"AE Renton","year":"2011","unstructured":"Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257\u2013268. \nhttps:\/\/doi.org\/10.1016\/j.neuron.2011.09.010","journal-title":"Neuron"},{"key":"2082_CR51","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1007\/s00401-015-1450-z","volume":"130","author":"MH Schludi","year":"2015","unstructured":"Schludi MH, May S, Grasser FA, Rentzsch K, Kremmer E, Kupper C et al (2015) Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol 130:537\u2013555. \nhttps:\/\/doi.org\/10.1007\/s00401-015-1450-z","journal-title":"Acta Neuropathol"},{"key":"2082_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4407","author":"R Sivadasan","year":"2016","unstructured":"Sivadasan R, Hornburg D, Drepper C, Frank N, Jablonka S, Hansel A et al (2016) C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nat Neurosci. \nhttps:\/\/doi.org\/10.1038\/nn.4407","journal-title":"Nat Neurosci"},{"key":"2082_CR53","doi-asserted-by":"publisher","first-page":"2390","DOI":"10.1158\/0008-5472.CAN-03-3207","volume":"64","author":"T Stiff","year":"2004","unstructured":"Stiff T, O'Driscoll M, Rief N, Iwabuchi K, Lobrich M, Jeggo PA (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 64:2390\u20132396","journal-title":"Cancer Res"},{"key":"2082_CR54","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1093\/hmg\/ddv005","volume":"24","author":"Z Tao","year":"2015","unstructured":"Tao Z, Wang H, Xia Q, Li K, Li K, Jiang X et al (2015) Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet 24:2426\u20132441. \nhttps:\/\/doi.org\/10.1093\/hmg\/ddv005","journal-title":"Hum Mol Genet"},{"key":"2082_CR55","doi-asserted-by":"publisher","first-page":"e1003429","DOI":"10.1371\/journal.pgen.1003429","volume":"9","author":"NA Tchurikov","year":"2013","unstructured":"Tchurikov NA, Kretova OV, Fedoseeva DM, Sosin DV, Grachev SA, Serebraykova MV et al (2013) DNA double-strand breaks coupled with PARP1 and HNRNPA2B1 binding sites flank coordinately expressed domains in human chromosomes. PLoS Genet 9:e1003429. \nhttps:\/\/doi.org\/10.1371\/journal.pgen.1003429","journal-title":"PLoS Genet"},{"key":"2082_CR56","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.ijrobp.2015.11.013","volume":"94","author":"A Granzotto","year":"2016","unstructured":"The COPERNIC project investigators, Granzotto A, Benadjaoud MA, Vogin G, Devic C, Ferlazzo ML et al (2016) Influence of nucleoshuttling of the ATM protein in the healthy tissues response to radiation therapy: toward a molecular classification of human radiosensitivity. Int J Radiat Oncol Biol Phys 94:450\u2013460. \nhttps:\/\/doi.org\/10.1016\/j.ijrobp.2015.11.013","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"2082_CR57","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1002\/humu.22244","volume":"34","author":"J van der Zee","year":"2013","unstructured":"van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, Engelborghs S et al (2013) A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat 34:363\u2013373. \nhttps:\/\/doi.org\/10.1002\/humu.22244","journal-title":"Hum Mutat"},{"key":"2082_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4604","author":"C Walker","year":"2017","unstructured":"Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W et al (2017) C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. \nhttps:\/\/doi.org\/10.1038\/nn.4604","journal-title":"Nat Neurosci"},{"key":"2082_CR59","volume-title":"Characterization of hnRNP A3 isoforms in the A2RE-proteome","author":"Y Wei","year":"2014","unstructured":"Wei Y (2014) Characterization of hnRNP A3 isoforms in the A2RE-proteome. School of Chemistry and Molecular Biosciences, The University of Queensland, City"},{"key":"2082_CR60","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/j.neuron.2014.12.010","volume":"84","author":"X Wen","year":"2014","unstructured":"Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y 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\u20131225. \nhttps:\/\/doi.org\/10.1016\/j.neuron.2014.12.010","journal-title":"Neuron"},{"key":"2082_CR61","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/nrm1127","volume":"4","author":"SC West","year":"2003","unstructured":"West SC (2003) Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 4:435\u2013445. \nhttps:\/\/doi.org\/10.1038\/nrm1127","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2082_CR62","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.03.019","author":"MR White","year":"2019","unstructured":"White MR, Mitrea DM, Zhang P, Stanley CB, Cassidy DE, Nourse A et al (2019) C9orf72 Poly(PR) dipeptide repeats disturb biomolecular phase separation and disrupt nucleolar function. Mol Cell. \nhttps:\/\/doi.org\/10.1016\/j.molcel.2019.03.019","journal-title":"Mol Cell"},{"key":"2082_CR63","doi-asserted-by":"publisher","first-page":"4653","DOI":"10.1074\/jbc.C113.502336","volume":"289","author":"B Zamiri","year":"2014","unstructured":"Zamiri B, Reddy K, Macgregor RB Jr, Pearson CE (2014) TMPyP4 porphyrin distorts RNA G-quadruplex structures of the disease-associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins. J Biol Chem 289:4653\u20134659. \nhttps:\/\/doi.org\/10.1074\/jbc.C113.502336","journal-title":"J Biol Chem"},{"key":"2082_CR64","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/s0002-9440(10)65396-5","volume":"154","author":"J Zhang","year":"1999","unstructured":"Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG et al (1999) Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol 154:1423\u20131429. \nhttps:\/\/doi.org\/10.1016\/s0002-9440(10)65396-5","journal-title":"Am J Pathol"},{"key":"2082_CR65","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nature14973","volume":"525","author":"K Zhang","year":"2015","unstructured":"Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P et al (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56\u201361. \nhttps:\/\/doi.org\/10.1038\/nature14973","journal-title":"Nature"},{"key":"2082_CR66","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/nn.4272","volume":"19","author":"YJ Zhang","year":"2016","unstructured":"Zhang YJ, Gendron TF, Grima JC, Sasaguri H, Jansen-West K, Xu YF et al (2016) C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci 19:668\u2013677. \nhttps:\/\/doi.org\/10.1038\/nn.4272","journal-title":"Nat Neurosci"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-019-02082-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00401-019-02082-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-019-02082-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T23:20:32Z","timestamp":1603322432000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00401-019-02082-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,23]]},"references-count":66,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1]]}},"alternative-id":["2082"],"URL":"https:\/\/doi.org\/10.1007\/s00401-019-02082-0","relation":{},"ISSN":["0001-6322","1432-0533"],"issn-type":[{"value":"0001-6322","type":"print"},{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,23]]},"assertion":[{"value":"29 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2019","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"CH collaborates with Denali Therapeutics on a topic not related to <i>C9orf72<\/i>, participated on one advisory board meeting of Biogen, and received a speaker honorarium from Novartis and Roche. All other authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants or participants\u2019 families included in this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}