{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T21:31:00Z","timestamp":1785879060433,"version":"3.56.0"},"reference-count":126,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T00:00:00Z","timestamp":1705449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Telethon Italia","award":["GMR22T1078"],"award-info":[{"award-number":["GMR22T1078"]}]},{"name":"Telethon Italia","award":["PRIN2020CL55XW"],"award-info":[{"award-number":["PRIN2020CL55XW"]}]},{"name":"Telethon Italia","award":["PRIN2022JKEBB8"],"award-info":[{"award-number":["PRIN2022JKEBB8"]}]},{"name":"Telethon Italia","award":["860035"],"award-info":[{"award-number":["860035"]}]},{"name":"Italian Ministry","award":["GMR22T1078"],"award-info":[{"award-number":["GMR22T1078"]}]},{"name":"Italian Ministry","award":["PRIN2020CL55XW"],"award-info":[{"award-number":["PRIN2020CL55XW"]}]},{"name":"Italian Ministry","award":["PRIN2022JKEBB8"],"award-info":[{"award-number":["PRIN2022JKEBB8"]}]},{"name":"Italian Ministry","award":["860035"],"award-info":[{"award-number":["860035"]}]},{"name":"European Union","award":["GMR22T1078"],"award-info":[{"award-number":["GMR22T1078"]}]},{"name":"European Union","award":["PRIN2020CL55XW"],"award-info":[{"award-number":["PRIN2020CL55XW"]}]},{"name":"European Union","award":["PRIN2022JKEBB8"],"award-info":[{"award-number":["PRIN2022JKEBB8"]}]},{"name":"European Union","award":["860035"],"award-info":[{"award-number":["860035"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Protein homeostasis is essential for neuron longevity, requiring a balanced regulation between protein synthesis and degradation. The clearance of misfolded and aggregated proteins, mediated by autophagy and the ubiquitin\u2013proteasome systems, maintains protein homeostasis in neurons, which are post-mitotic and thus cannot use cell division to diminish the burden of misfolded proteins. When protein clearance pathways are overwhelmed or otherwise disrupted, the accumulation of misfolded or aggregated proteins can lead to the activation of ER stress and the formation of stress granules, which predominantly attempt to restore the homeostasis by suppressing global protein translation. Alterations in these processes have been widely reported among studies investigating the toxic function of dipeptide repeats (DPRs) produced by G4C2 expansion in the C9orf72 gene of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this review, we outline the modalities of DPR-induced disruptions in protein homeostasis observed in a wide range of models of C9orf72-linked ALS\/FTD. We also discuss the relative importance of each DPR for toxicity, possible synergies between DPRs, and discuss the possible functional relevance of DPR aggregation to disease pathogenesis. Finally, we highlight the interdependencies of the observed effects and reflect on the importance of feedback and feedforward mechanisms in their contribution to disease progression. A better understanding of DPR-associated disease pathogenesis discussed in this review might shed light on disease vulnerabilities that may be amenable with therapeutic interventions.<\/jats:p>","DOI":"10.3390\/cells13020178","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T10:39:47Z","timestamp":1705487987000},"page":"178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["ALS\u2019 Perfect Storm: C9orf72-Associated Toxic Dipeptide Repeats as Potential Multipotent Disruptors of Protein Homeostasis"],"prefix":"10.3390","volume":"13","author":[{"given":"Paulien H.","family":"Smeele","sequence":"first","affiliation":[{"name":"Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Cesare","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6231-7105","authenticated-orcid":false,"given":"Thomas","family":"Vaccari","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-019-0101-y","article-title":"The proteostasis network and its decline in ageing","volume":"20","author":"Hipp","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","article-title":"Converging mechanisms in als and FTD: Disrupted RNA and protein homeostasis","volume":"79","author":"Ling","year":"2013","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3389\/fnins.2020.00042","article-title":"The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","volume":"14","author":"Abramzon","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3109\/21678421.2013.838586","article-title":"Intermediate repeat expansion length in C9orf72 may be pathological in amyotrophic lateral sclerosis","volume":"15","author":"Byrne","year":"2014","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_8","first-page":"e15","article-title":"Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis","volume":"38","author":"Chen","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s40478-019-0724-4","article-title":"C9orf72 intermediate expansions of 24\u201330 repeats are associated with ALS","volume":"7","author":"Iacoangeli","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"661447","DOI":"10.3389\/fncel.2021.661447","article-title":"C9ORF72: What It Is, What It Does, and Why It Matters","volume":"15","author":"Smeyers","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s00401-013-1147-0","article-title":"Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia","volume":"126","author":"Fratta","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/ana.24453","article-title":"C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits","volume":"78","author":"Koppers","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s00401-014-1336-5","article-title":"Aggregation-prone c9FTD\/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress","volume":"128","author":"Zhang","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1093\/hmg\/ddu576","article-title":"Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD\/ALS","volume":"24","author":"Yamakawa","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00401-014-1329-4","article-title":"C9orf72 FTLD\/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration","volume":"128","author":"May","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1126\/science.aaa9344","article-title":"C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits","volume":"348","author":"Chew","year":"2015","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"107616","DOI":"10.1016\/j.celrep.2020.107616","article-title":"Hexanucleotide Repeat Expansions in c9FTD\/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo","volume":"31","author":"Todd","year":"2020","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s00401-017-1796-5","article-title":"A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism","volume":"135","author":"Swinnen","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s40478-018-0629-7","article-title":"Stable transgenic C9orf72 zebrafish model key aspects of the ALS\/FTD phenotype and reveal novel pathological features","volume":"6","author":"Shaw","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1126\/science.1256800","article-title":"C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins","volume":"345","author":"Mizielinska","year":"2014","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nature14974","article-title":"GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport","volume":"525","author":"Freibaum","year":"2015","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1007\/s00401-013-1200-z","article-title":"C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci","volume":"126","author":"Mizielinska","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/j.celrep.2013.10.049","article-title":"Hexanucleotide repeats in ALS\/FTD form length-dependent RNA Foci, sequester RNA binding proteins, and are neurotoxic","volume":"5","author":"Lee","year":"2013","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s00401-015-1429-9","article-title":"Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy","volume":"130","author":"Higginbottom","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E4968","DOI":"10.1073\/pnas.1315438110","article-title":"RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia","volume":"110","author":"Zu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s00401-013-1192-8","article-title":"Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD\/ALS","volume":"126","author":"Gendron","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1007\/s00401-013-1189-3","article-title":"Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins","volume":"126","author":"Mori","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1126\/science.1232927","article-title":"The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD\/ALS","volume":"339","author":"Mori","year":"2013","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.neuron.2013.02.004","article-title":"Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD\/ALS","volume":"77","author":"Ash","year":"2013","journal-title":"Neuron"},{"key":"ref_30","first-page":"68","article-title":"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","volume":"2","author":"Mann","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s00401-015-1450-z","article-title":"Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing","volume":"130","author":"Schludi","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12192-017-0806-9","article-title":"The small heat shock protein B8 (HSPB8) efficiently removes aggregating species of dipeptides produced in C9ORF72-related neurodegenerative diseases","volume":"23","author":"Cristofani","year":"2018","journal-title":"Cell Stress Chaperones"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"696.e12","DOI":"10.1016\/j.cell.2017.12.030","article-title":"In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment","volume":"172","author":"Guo","year":"2018","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e102811","DOI":"10.15252\/embj.2019102811","article-title":"Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS\/FTD","volume":"39","author":"Khosravi","year":"2020","journal-title":"EMBO J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/nn.4272","article-title":"C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins","volume":"19","author":"Zhang","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"ENEURO.0249-16.2017","DOI":"10.1523\/ENEURO.0249-16.2017","article-title":"The proline\/arginine dipeptide from hexanucleotide repeat expanded C9ORF72 inhibits the proteasome","volume":"4","author":"Gupta","year":"2017","journal-title":"eNeuro"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1093\/jnen\/nlad078","article-title":"C9orf72 proline-arginine dipeptide repeats disrupt the proteasome and perturb proteolytic activities","volume":"82","author":"Zhang","year":"2023","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_38","first-page":"1263","article-title":"Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species","volume":"127","author":"Scotter","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Van Eersel, J., Ke, Y.D., Gladbach, A., Bi, M., G\u00f6tz, J., Kril, J.J., and Ittner, L.M. (2011). Cytoplasmic accumulation and aggregation of TDP-43 upon proteasome inhibition in cultured neurons. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022850"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s00401-013-1181-y","article-title":"Dipeptide repeat protein pathology in C9ORF72 mutation cases: Clinico-pathological correlations","volume":"126","author":"MacKenzie","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40478-015-0218-y","article-title":"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","volume":"3","author":"Lee","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/nan.12178","article-title":"Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene","volume":"41","author":"Baborie","year":"2015","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.1093\/brain\/aww250","article-title":"Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia","volume":"139","author":"Vatsavayai","year":"2016","journal-title":"Brain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/s41580-020-0241-0","article-title":"Mechanisms governing autophagosome biogenesis","volume":"21","author":"Nakatogawa","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev-cellbio-100818-125242","article-title":"Autophagy in neurons","volume":"35","author":"Stavoe","year":"2019","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.1174447","article-title":"A gene network regulating lysosomal biogenesis and function","volume":"325","author":"Sardiello","year":"2009","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e59419","DOI":"10.7554\/eLife.59419","article-title":"Tfeb\/mitf links impaired nuclear import to autophagolysosomal dysfunction in c9-als","volume":"9","author":"Cunningham","year":"2020","journal-title":"eLife"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1080\/15548627.2023.2249750","article-title":"Disrupted endoplasmic reticulum-mediated autophagosomal biogenesis in a Drosophila model of C9-ALS-FTD","volume":"20","author":"Sung","year":"2023","journal-title":"Autophagy"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1080\/15548627.2022.2063003","article-title":"Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1\/sigma-1 receptor chaperone by pridopidine","volume":"19","author":"Wang","year":"2023","journal-title":"Autophagy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1080\/19491034.2016.1172152","article-title":"Nucleocytoplasmic transport in C9orf72-mediated ALS\/FTD","volume":"7","author":"Zhang","year":"2016","journal-title":"Nucleus"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature14973","article-title":"The C9orf72 repeat expansion disrupts nucleocytoplasmic transport","volume":"525","author":"Zhang","year":"2015","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.neuron.2020.06.027","article-title":"G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS\/FTD","volume":"107","author":"Coyne","year":"2020","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"E1111","DOI":"10.1073\/pnas.1620293114","article-title":"Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export","volume":"114","author":"Shi","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"eabb3774","DOI":"10.1126\/scitranslmed.abb3774","article-title":"C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy","volume":"12","author":"Cook","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1126\/science.1204592","article-title":"TFEB links autophagy to lysosomal biogenesis","volume":"332","author":"Settembre","year":"2011","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1080\/15548627.2015.1134081","article-title":"Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway","volume":"12","author":"Espinosa","year":"2016","journal-title":"Autophagy"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1080\/15548627.2015.1134080","article-title":"Control of lysosomal biogenesis and Notch-dependent tissue patterning by components of the TFEB-V-ATPase axis in Drosophila melanogaster","volume":"12","author":"Tognon","year":"2016","journal-title":"Autophagy"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1093\/brain\/awab300","article-title":"Interactome screening of C9orf72 dipeptide repeats reveals VCP sequestration and functional impairment by polyGA","volume":"145","author":"Motaln","year":"2022","journal-title":"Brain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.15252\/embj.201694401","article-title":"The C9orf72 protein interacts with Rab1a and the ULK 1 complex to regulate initiation of autophagy","volume":"35","author":"Webster","year":"2016","journal-title":"EMBO J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e1601167","DOI":"10.1126\/sciadv.1601167","article-title":"A C9ORF72\/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy","volume":"2","author":"Yang","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s40478-016-0324-5","article-title":"The ALS\/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway","volume":"4","author":"Sullivan","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1080\/21541248.2016.1212688","article-title":"C9ORF72 is a GDP\/GTP exchange factor for Rab8 and Rab39 and regulates autophagy","volume":"8","author":"Corbier","year":"2017","journal-title":"Small GTPases"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1080\/21541248.2016.1240495","article-title":"C9orf72 plays a central role in Rab GTPase-dependent regulation of autophagy","volume":"9","author":"Webster","year":"2018","journal-title":"Small GTPases"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e13126","DOI":"10.1111\/acel.13126","article-title":"C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis","volume":"19","author":"Wang","year":"2020","journal-title":"Aging Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e100574","DOI":"10.15252\/embj.2018100574","article-title":"Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders","volume":"39","author":"Boivin","year":"2020","journal-title":"EMBO J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e5815","DOI":"10.7717\/peerj.5815","article-title":"C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor","volume":"2018","author":"Iyer","year":"2018","journal-title":"PeerJ"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e202101276","DOI":"10.26508\/lsa.202101276","article-title":"C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons","volume":"5","author":"Marchi","year":"2022","journal-title":"Life Sci. Alliance"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.celrep.2016.09.032","article-title":"Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS\/FTD","volume":"17","author":"Westergard","year":"2016","journal-title":"Cell Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4903","DOI":"10.1074\/jbc.M115.694273","article-title":"The glycine-alanine dipeptide repeat from C9 or f72 hexanucleotide expansions forms toxic amyloids possessing cell-to-cell transmission properties","volume":"291","author":"Chang","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"687","DOI":"10.15252\/emmm.201607054","article-title":"Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins","volume":"9","author":"Zhou","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Matus, S., Valenzuela, V., Medinas, D.B., and Hetz, C. (2013). ER dysfunction and protein folding stress in ALS. Int. J. Cell Biol., 2013.","DOI":"10.1155\/2013\/674751"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/nn.4065","article-title":"Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS","volume":"18","author":"Prudencio","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/bpa.12894","article-title":"Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells","volume":"31","author":"Meeter","year":"2021","journal-title":"Brain Pathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s00401-022-02494-5","article-title":"PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS\/FTD","volume":"144","author":"Pilotto","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41588-018-0070-7","article-title":"CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity","volume":"50","author":"Kramer","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s12264-019-00395-4","article-title":"Poly-PR in C9ORF72-Related Amyotrophic Lateral Sclerosis\/Frontotemporal Dementia Causes Neurotoxicity by Clathrin-Dependent Endocytosis","volume":"35","author":"Wang","year":"2019","journal-title":"Neurosci. Bull."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"18591","DOI":"10.1073\/pnas.2005748117","article-title":"Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS\/FTD mice","volume":"117","author":"Zu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1038\/s41591-018-0071-1","article-title":"Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis","volume":"24","author":"Zhang","year":"2018","journal-title":"Nat. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.1523\/JNEUROSCI.1799-22.2023","article-title":"c-Jun N-Terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-Mediated ALS and FTD","volume":"43","author":"Sahana","year":"2023","journal-title":"J. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1038\/s41467-017-02200-0","article-title":"RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response","volume":"8","author":"Green","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41467-017-02495-z","article-title":"C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2\u03b1 phosphorylation","volume":"9","author":"Cheng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.1038\/s41467-021-26303-x","article-title":"A C. elegans model of C9orf72-associated ALS\/FTD uncovers a conserved role for eIF2D in RAN translation","volume":"12","author":"Sonobe","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.nbd.2018.05.009","article-title":"Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress","volume":"116","author":"Sonobe","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e9423","DOI":"10.15252\/emmm.201809423","article-title":"Repeat-associated non- AUG translation in C9orf72- ALS\/FTD is driven by neuronal excitation and stress","volume":"11","author":"Westergard","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1093\/hmg\/ddab098","article-title":"The alternative initiation factor eIF2A plays key role in RAN translation of myotonic dystrophy type 2 CCUG\u2022CAGG repeats","volume":"30","author":"Tusi","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7289","DOI":"10.7150\/thno.76138","article-title":"C9orf72 regulates the unfolded protein response and stress granule formation by interacting with eIF2\u03b1","volume":"12","author":"Zheng","year":"2022","journal-title":"Theranostics"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1093\/hmg\/ddw052","article-title":"Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation","volume":"25","author":"Kanekura","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s00401-018-1946-4","article-title":"C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A","volume":"137","author":"Moens","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.1038\/s41467-022-30418-0","article-title":"Ribosome inhibition by C9ORF72-ALS\/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM","volume":"13","author":"Loveland","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tibs.2007.12.003","article-title":"Stress granules: The Tao of RNA triage","volume":"33","author":"Anderson","year":"2008","journal-title":"Trends Biochem. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.molcel.2009.11.020","article-title":"Eukaryotic Stress Granules: The Ins and Outs of Translation","volume":"36","author":"Buchan","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.semcdb.2022.09.013","article-title":"An emerging role for the endoplasmic reticulum in stress granule biogenesis","volume":"156","author":"Nicchitta","year":"2022","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.cell.2016.10.002","article-title":"C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles","volume":"167","author":"Lee","year":"2016","journal-title":"Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"789.e12","DOI":"10.1016\/j.cell.2016.10.003","article-title":"Toxic PR Poly-Dipeptides Encoded by the C9orf72 Repeat Expansion Target LC Domain Polymers","volume":"167","author":"Lin","year":"2016","journal-title":"Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.molcel.2017.02.013","article-title":"Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics","volume":"65","author":"Boeynaems","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13024-019-0310-z","article-title":"Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy","volume":"14","author":"Chew","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1002\/stem.2388","article-title":"C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell-Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","volume":"34","author":"Dafinca","year":"2016","journal-title":"Stem Cells"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41580-020-00326-6","article-title":"Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing","volume":"22","author":"Alberti","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e201800070","DOI":"10.26508\/lsa.201800070","article-title":"Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR\/PR interactors driving toxicity","volume":"1","author":"Hartmann","year":"2018","journal-title":"Life Sci. Alliance"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Baradaran-Heravi, Y., Van Broeckhoven, C., and van der Zee, J. (2020). Stress granule mediated protein aggregation and underlying gene defects in the FTD-ALS spectrum. Neurobiol. Dis., 134.","DOI":"10.1016\/j.nbd.2019.104639"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.cell.2020.03.046","article-title":"G3BP1 Is a Tunable Switch that Triggers Phase Separation to Assemble Stress Granules","volume":"181","author":"Yang","year":"2020","journal-title":"Cell"},{"key":"ref_102","first-page":"346.e17","article-title":"RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation","volume":"181","author":"Kopach","year":"2020","journal-title":"Cell"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"306.e28","DOI":"10.1016\/j.cell.2020.03.050","article-title":"Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization","volume":"181","author":"Sanders","year":"2020","journal-title":"Cell"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"112822","DOI":"10.1016\/j.celrep.2023.112822","article-title":"Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions","volume":"42","author":"Park","year":"2023","journal-title":"Cell Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2015.09.015","article-title":"Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization","volume":"163","author":"Molliex","year":"2015","journal-title":"Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.cell.2015.07.047","article-title":"A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation","volume":"162","author":"Patel","year":"2015","journal-title":"Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"808.e9","DOI":"10.1016\/j.neuron.2017.07.025","article-title":"TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics","volume":"95","author":"Mackenzie","year":"2017","journal-title":"Neuron"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.15252\/embj.201695957","article-title":"An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function","volume":"36","author":"Mateju","year":"2017","journal-title":"EMBO J."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e2014188118","DOI":"10.1073\/pnas.2014188118","article-title":"TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau","volume":"118","author":"Ash","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.neuron.2014.12.010","article-title":"Antisense Proline-Arginine RAN dipeptides linked to C9ORF72- ALS\/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death","volume":"84","author":"Xinmei","year":"2014","journal-title":"Neuron"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00401-017-1711-0","article-title":"Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss","volume":"134","author":"Schludi","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00401-020-02176-0","article-title":"Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS","volume":"140","author":"LaClair","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1007\/s00401-015-1476-2","article-title":"Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers","volume":"130","author":"Mackenzie","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/2051-5960-2-70","article-title":"Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72","volume":"2","author":"Davidson","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s40478-018-0564-7","article-title":"Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease","volume":"6","author":"Sakae","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00401-017-1793-8","article-title":"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","volume":"135","author":"Saberi","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e202201739","DOI":"10.26508\/lsa.202201739","article-title":"Toxicity of C9orf72-associated dipeptide repeat peptides is modified by commonly used protein tags","volume":"6","author":"Fischer","year":"2023","journal-title":"Life Sci. Alliance"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4765","DOI":"10.1093\/hmg\/ddx350","article-title":"C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity","volume":"26","author":"Lee","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s00401-015-1448-6","article-title":"FTD\/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions","volume":"130","author":"Yang","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1101\/gad.992302","article-title":"ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats","volume":"16","author":"Nishitoh","year":"2002","journal-title":"Genes Dev."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"14189","DOI":"10.1074\/jbc.M413660200","article-title":"Phosphorylation of the \u03b1-subunit of the eukaryotic initiation factor-2 (eIF2\u03b1) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition","volume":"280","author":"Jiang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1038\/cdd.2014.103","article-title":"Inhibition of autophagy, lysosome and VCP function impairs stress granule assembly","volume":"21","author":"Seguin","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1091\/mbc.e06-12-1079","article-title":"Inhibition of the ubiquitin-proteasome system induces stress granule formation","volume":"18","author":"Mazroui","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.cell.2013.05.037","article-title":"XEukaryotic stress granules are cleared by autophagy and Cdc48\/VCP function","volume":"153","author":"Buchan","year":"2013","journal-title":"Cell"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1080\/15548627.2022.2164427","article-title":"Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules","volume":"19","author":"Yang","year":"2023","journal-title":"Autophagy"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"958.e17","DOI":"10.1016\/j.cell.2018.03.025","article-title":"Stress Granule Assembly Disrupts Nucleocytoplasmic Transport","volume":"173","author":"Zhang","year":"2018","journal-title":"Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/2\/178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:49:02Z","timestamp":1760104142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/2\/178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,17]]},"references-count":126,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["cells13020178"],"URL":"https:\/\/doi.org\/10.3390\/cells13020178","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,17]]}}}