{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T10:28:06Z","timestamp":1792232886635,"version":"4.4.0"},"reference-count":130,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Neurology and Neurosciences, Rutgers University New Jersey Medical School"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal adult neurodegenerative disorder. Since no cure has been found, finding effective therapeutic targets for ALS remains a major challenge. Gene C9orf72 mutations with the formation of hexanucleotide repeat (GGGGCC) expansion (HRE) have been considered the most common genetic pathogenesis of ALS. The literature review indicates that the C9orf72 HRE causes both the gain-of-function toxicity and loss of function of C9ORF72. The formation of RNA foci and dipeptide repeats (DPRs) resulting from HRE is responsible for toxic function gain. The RNA foci can interfere with RNA processing, while DPRs directly bind to and sequester associated proteins to disrupt processes of rRNA synthesis, mRNA translation, autophagy, and nucleocytoplasmic transport. The mutations of C9orf72 and HRE result in the loss of functional C9ORF72. Under physiological conditions, C9ORF72 binds to Smith\u2013Magenis chromosome region 8 and WD repeat-containing protein and forms a protein complex. Loss of C9ORF72 leads to autophagic impairment, increased oxidative stress, nucleocytoplasmic transport impairment, and inflammatory response. The attempted treatments for ALS have been tried by targeting C9orf72 HRE; however, the outcomes are far from satisfactory yet. More studies should be performed on pharmacological and molecular modulators against C9orf72 HRE to evaluate their efficacy by targeting HRE.<\/jats:p>","DOI":"10.3390\/ijms26094276","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T09:16:12Z","timestamp":1746090972000},"page":"4276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Targeting Gene C9orf72 Pathogenesis for Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"26","author":[{"given":"Zhao Zhong","family":"Chong","sequence":"first","affiliation":[{"name":"Department of Neurology, New Jersey Medical School, Rutgers University, 185 S Orange, Newark, NJ 07103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizar","family":"Souayah","sequence":"additional","affiliation":[{"name":"Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e542","DOI":"10.1212\/NXG.0000000000000542","article-title":"C9orf72 and the Care of the Patient with ALS or FTD: Progress and Recommendations After 10 Years","volume":"7","author":"Roggenbuck","year":"2021","journal-title":"Neurol. Genet."},{"key":"ref_3","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_4","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_5","doi-asserted-by":"crossref","first-page":"e200079","DOI":"10.1212\/NXG.0000000000200079","article-title":"Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies","volume":"9","author":"Dou","year":"2023","journal-title":"Neurol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/brain\/awr353","article-title":"The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions","volume":"135","author":"Dopper","year":"2012","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/S1474-4422(11)70261-7","article-title":"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","volume":"11","author":"Gijselinck","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Smeyers, J., Banchi, E.G., and Latouche, M. (2021). C9ORF72: What It Is, What It Does, and Why It Matters. Front. Cell Neurosci., 15.","DOI":"10.3389\/fncel.2021.661447"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s40478-016-0306-7","article-title":"C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers","volume":"4","author":"Rizzu","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2950.e5","DOI":"10.1016\/j.neurobiolaging.2012.07.005","article-title":"Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype","volume":"33","author":"Rutherford","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00401-015-1473-5","article-title":"A 30-unit hexanucleotide repeat expansion in C9orf72 induces pathological lesions with dipeptide-repeat proteins and RNA foci, but not TDP-43 inclusions and clinical disease","volume":"130","author":"Gami","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01677063.2024.2343672","article-title":"Meta-analysis of the association between C9orf72 repeats and neurodegeneration diseases","volume":"38","author":"Jin","year":"2024","journal-title":"J. Neurogenet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/mp.2015.159","article-title":"The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter","volume":"21","author":"Gijselinck","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nagy, Z.F., Pal, M., Engelhardt, J.I., Molnar, M.J., Klivenyi, P., and Szell, M. (2024). Beyond C9orf72: Repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations. BMC Med. Genom., 17.","DOI":"10.1186\/s12920-024-01807-9"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"217.e15","DOI":"10.1016\/j.neurobiolaging.2015.11.016","article-title":"Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis","volume":"38","author":"Chen","year":"2016","journal-title":"Neurobiol. Aging."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yang, Q., Jiao, B., and Shen, L. (2020). The Development of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disorders. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.562758"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1080\/15548627.2024.2340415","article-title":"Toxic gain-of-function mechanisms in C9orf72 ALS-FTD neurons drive autophagy and lysosome dysfunction","volume":"20","author":"Beckers","year":"2024","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2128232024","DOI":"10.1523\/JNEUROSCI.2128-23.2024","article-title":"C9ORF72 Deficiency Results in Neurodegeneration in the Zebrafish Retina","volume":"44","author":"Jaroszynska","year":"2024","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Freibaum, B.D., and Taylor, J.P. (2017). The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00035"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-023-02652-3","article-title":"G(2)C(4) targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in human C9orf72 ALS\/FTD induced pluripotent stem cell derived neurons","volume":"147","author":"Rothstein","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"102441","DOI":"10.1016\/j.arr.2024.102441","article-title":"TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: From pathomechanisms to therapeutic strategies","volume":"100","author":"Ho","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00401-022-02471-y","article-title":"HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS","volume":"144","author":"Braems","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1080\/21678421.2017.1349152","article-title":"Mutation in the RRM2 domain of TDP-43 in Amyotrophic Lateral Sclerosis with rapid progression associated with ubiquitin positive aggregates in cultured motor neurons","volume":"19","author":"Maurel","year":"2018","journal-title":"Amyotroph. Lateral Scler. Frontotemporal Degener."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103900","DOI":"10.1016\/j.isci.2022.103900","article-title":"Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology","volume":"25","author":"Sprunger","year":"2022","journal-title":"iScience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"218.e3","DOI":"10.1016\/j.neurobiolaging.2015.11.023","article-title":"MATR3 mutation analysis in a Chinese cohort with sporadic amyotrophic lateral sclerosis","volume":"38","author":"Xu","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.neuron.2013.10.015","article-title":"RNA toxicity from the ALS\/FTD C9ORF72 expansion is mitigated by antisense intervention","volume":"80","author":"Donnelly","year":"2013","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s00401-013-1235-1","article-title":"Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia","volume":"127","author":"Stepto","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1158\/1541-7786.MCR-14-0131","article-title":"Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer","volume":"12","author":"Das","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/978-3-319-60733-7_6","article-title":"RNA Nuclear Export: From Neurological Disorders to Cancer","volume":"1007","author":"Hautbergue","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16063","DOI":"10.1038\/ncomms16063","article-title":"SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits","volume":"8","author":"Hautbergue","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e19032","DOI":"10.7554\/eLife.19032","article-title":"Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106","volume":"6","author":"Celona","year":"2017","journal-title":"Elife"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nrneurol.2014.78","article-title":"The role of FUS gene variants in neurodegenerative diseases","volume":"10","author":"Deng","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2220020121","DOI":"10.1073\/pnas.2220020121","article-title":"Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats","volume":"121","author":"Celona","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","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_36","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nature13124","article-title":"C9orf72 nucleotide repeat structures initiate molecular cascades of disease","volume":"507","author":"Haeusler","year":"2014","journal-title":"Nature"},{"key":"ref_37","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_38","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_39","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1042\/ETLS20190167","article-title":"Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS\/FTD","volume":"4","author":"Odeh","year":"2020","journal-title":"Emerg. Top. Life Sci."},{"key":"ref_40","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_41","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_42","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_43","doi-asserted-by":"crossref","first-page":"eadl1030","DOI":"10.1126\/scisignal.adl1030","article-title":"Poly-GR repeats associated with ALS\/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons","volume":"17","author":"Dong","year":"2024","journal-title":"Sci. Signal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1038\/s41467-020-17129-0","article-title":"C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression","volume":"11","author":"Sun","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13024-020-00365-9","article-title":"Dipeptide repeat proteins inhibit homology-directed DNA double strand break repair in C9ORF72 ALS\/FTD","volume":"15","author":"Andrade","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev-biochem-060208-105251","article-title":"Functions and regulation of RNA editing by ADAR deaminases","volume":"79","author":"Nishikura","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1111\/jnc.15445","article-title":"Proline-arginine poly-dipeptide encoded by the C9orf72 repeat expansion inhibits adenosine deaminase acting on RNA","volume":"158","author":"Suzuki","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.nbd.2011.12.033","article-title":"Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons","volume":"45","author":"Hideyama","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_49","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_50","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":"Tg","year":"2023","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.neuron.2016.09.015","article-title":"Poly(GR) in C9ORF72-Related ALS\/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons","volume":"92","author":"Lu","year":"2016","journal-title":"Neuron"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Jimenez-Villegas, J., Kirby, J., Mata, A., Cadenas, S., Turner, M.R., Malaspina, A., Shaw, P.J., Cuadrado, A., and Rojo, A.I. (2022). Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance. Antioxidants, 11.","DOI":"10.3390\/antiox11101897"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Cicardi, M.E., Hallgren, J.H., Mawrie, D., Krishnamurthy, K., Markandaiah, S.S., Nelson, A.T., Kankate, V., Anderson, E.N., Pasinelli, P., and Pandey, U.B. (2023). C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress. bioRxiv, 26.","DOI":"10.1101\/2023.02.16.528809"},{"key":"ref_54","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":"2024","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"10318","DOI":"10.1007\/s12035-024-04187-4","article-title":"C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS\/FTD","volume":"61","author":"Sultana","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"ENEURO","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_58","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_59","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1016\/j.apsb.2024.02.004","article-title":"ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction","volume":"14","author":"Xu","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1126\/science.aaa9344","article-title":"Neurodegeneration. 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_61","doi-asserted-by":"crossref","first-page":"112133","DOI":"10.1016\/j.celrep.2023.112133","article-title":"Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome","volume":"42","author":"Shu","year":"2023","journal-title":"Cell Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.1093\/hmg\/ddaa209","article-title":"Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions","volume":"29","author":"Liu","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"fcae282","DOI":"10.1093\/braincomms\/fcae282","article-title":"C9orf72 dipeptides activate the NLRP3 inflammasome","volume":"6","author":"Hoyle","year":"2024","journal-title":"Brain Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"RP89694","DOI":"10.7554\/eLife.89694","article-title":"C9orf72 polyPR directly binds to various nuclear transport components","volume":"12","author":"Jafarinia","year":"2024","journal-title":"Elife"},{"key":"ref_65","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_66","doi-asserted-by":"crossref","unstructured":"Geng, Y., and Cai, Q. (2024). Role of C9orf72 hexanucleotide repeat expansions in ALS\/FTD pathogenesis. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1322720"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Steffke, C., Agarwal, S., Kabashi, E., and Catanese, A. (2024). Overexpression of Toxic Poly(Glycine-Alanine) Aggregates in Primary Neuronal Cultures Induces Time-Dependent Autophagic and Synaptic Alterations but Subtle Activity Impairments. Cells, 13.","DOI":"10.3390\/cells13151300"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e10722","DOI":"10.15252\/emmm.201910722","article-title":"Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS\/FTD is rescued by SV2 replenishment","volume":"12","author":"Jensen","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e2113813119","DOI":"10.1073\/pnas.2113813119","article-title":"Poly-dipeptides produced from C9orf72 hexanucleotide repeats cause selective motor neuron hyperexcitability in ALS","volume":"119","author":"Jo","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s41586-020-2633-x","article-title":"Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD","volume":"585","author":"Su","year":"2020","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1080\/15548627.2020.1779473","article-title":"The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases","volume":"16","author":"Tang","year":"2020","journal-title":"Autophagy"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.brainres.2016.04.062","article-title":"C9orf72 isoforms in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration","volume":"1647","author":"Xiao","year":"2016","journal-title":"Brain Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1091\/mbc.e16-01-0003","article-title":"C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling","volume":"27","author":"Amick","year":"2016","journal-title":"Mol. Biol. Cell."},{"key":"ref_74","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 eIF2alpha","volume":"12","author":"Zheng","year":"2022","journal-title":"Theranostics"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/ana.23946","article-title":"Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis","volume":"74","author":"Ciura","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Therrien, M., Rouleau, G.A., Dion, P.A., and Parker, J.A. (2013). Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0083450"},{"key":"ref_77","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_78","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.1080\/15548627.2021.1872189","article-title":"C9orf72 ALS-FTD: Recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels","volume":"17","author":"Beckers","year":"2021","journal-title":"Autophagy"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Diab, R., Pilotto, F., and Saxena, S. (2023). Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology. Front. Cell Neurosci., 17.","DOI":"10.3389\/fncel.2023.1086895"},{"key":"ref_80","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_81","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.15252\/embj.201593350","article-title":"Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death","volume":"35","author":"Sellier","year":"2016","journal-title":"EMBO J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00401-013-1090-0","article-title":"Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: Genetics and neuropathology","volume":"125","author":"Teyssou","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s40478-019-0694-6","article-title":"HR23B pathology preferentially co-localizes with p62, pTDP-43 and poly-GA in C9ORF72-linked frontotemporal dementia and amyotrophic lateral sclerosis","volume":"7","author":"Riemslagh","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1038\/s41467-018-05273-7","article-title":"A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy","volume":"9","author":"Chitiprolu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/bioinformatics\/bts725","article-title":"The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs","volume":"29","author":"Levine","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_86","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":"6","author":"Iyer","year":"2018","journal-title":"PeerJ"},{"key":"ref_87","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_88","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/jnc.15255","article-title":"Cellular and physiological functions of C9ORF72 and implications for ALS\/FTD","volume":"157","author":"Pang","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1083\/jcb.201111079","article-title":"TBC1D14 regulates autophagosome formation via Rab11- and ULK1-positive recycling endosomes","volume":"197","author":"Longatti","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/j.1600-0854.2007.00677.x","article-title":"Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells","volume":"9","author":"Fader","year":"2008","journal-title":"Traffic"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1091\/mbc.e13-10-0574","article-title":"Rab11 facilitates cross-talk between autophagy and endosomal pathway through regulation of Hook localization","volume":"25","author":"Szatmari","year":"2014","journal-title":"Mol. Biol. Cell."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1093\/hmg\/ddu068","article-title":"C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking","volume":"23","author":"Farg","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.molmed.2012.11.001","article-title":"mTOR: On target for novel therapeutic strategies in the nervous system","volume":"19","author":"Maiese","year":"2013","journal-title":"Trends Mol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.2174\/1389450116666150408103448","article-title":"mTOR: A Novel Therapeutic Target for Diseases of Multiple Systems","volume":"16","author":"Chong","year":"2015","journal-title":"Curr. Drug Targets"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1007\/s00726-016-2171-x","article-title":"Rag GTPase in amino acid signaling","volume":"48","author":"Kim","year":"2016","journal-title":"Amino Acids"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Dossou, A.S., and Basu, A. (2019). The Emerging Roles of mTORC1 in Macromanaging Autophagy. Cancers, 11.","DOI":"10.3390\/cancers11101422"},{"key":"ref_97","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_98","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.devcel.2008.02.005","article-title":"Signaling to nuclear transport","volume":"14","author":"Clarke","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"112134","DOI":"10.1016\/j.celrep.2023.112134","article-title":"Loss of C9orf72 perturbs the Ran-GTPase gradient and nucleocytoplasmic transport, generating compositionally diverse Importin beta-1 granules","volume":"42","author":"McGoldrick","year":"2023","journal-title":"Cell Rep."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Femiano, C., Bruno, A., Gilio, L., Buttari, F., Dolcetti, E., Galifi, G., Azzolini, F., Borrelli, A., Furlan, R., and Finardi, A. (2024). Inflammatory signature in amyotrophic lateral sclerosis predicting disease progression. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-67165-9"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/j.1468-1331.2009.02560.x","article-title":"Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis","volume":"16","author":"Kuhle","year":"2009","journal-title":"Eur. J. Neurol."},{"key":"ref_102","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_103","doi-asserted-by":"crossref","first-page":"5898","DOI":"10.1038\/s41467-023-41603-0","article-title":"C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9","volume":"14","author":"Vahsen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Atanasio, A., Decman, V., White, D., Ramos, M., Ikiz, B., Lee, H.C., Siao, C.J., Brydges, S., LaRosa, E., and Bai, Y. (2016). C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci. Rep., 6.","DOI":"10.1038\/srep23204"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Fang, T., Je, G., Pacut, P., Keyhanian, K., Gao, J., and Ghasemi, M. (2022). Gene Therapy in Amyotrophic Lateral Sclerosis. Cells, 11.","DOI":"10.3390\/cells11132066"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.neuron.2016.04.006","article-title":"Gain of Toxicity from ALS\/FTD-Linked Repeat Expansions in Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs","volume":"90","author":"Jiang","year":"2016","journal-title":"Neuron"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/s41467-021-21112-8","article-title":"Variant-selective stereopure oligonucleotides protect against pathologies associated with -repeat expansion in preclinical models","volume":"12","author":"Liu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S1474-4422(24)00216-3","article-title":"Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: A phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study","volume":"23","author":"Rothstein","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.omtn.2022.04.007","article-title":"Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD","volume":"28","author":"Liu","year":"2022","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41591-021-01557-6","article-title":"Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide","volume":"28","author":"Tran","year":"2022","journal-title":"Nat. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1038\/s41467-022-33332-7","article-title":"CRISPR\/Cas9-mediated excision of ALS\/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro","volume":"13","author":"Meijboom","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1093\/hmg\/ddaa106","article-title":"Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR\/Cas9 genome editing using homology-directed repair","volume":"29","author":"Ababneh","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e179016","DOI":"10.1172\/JCI179016","article-title":"CRISPR\/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA","volume":"134","author":"Liu","year":"2024","journal-title":"J. Clin. Invest."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.neuron.2019.09.003","article-title":"CRISPR-Cas9 Screens Identify the RNA Helicase DDX3X as a Repressor of C9ORF72 (GGGGCC)n Repeat-Associated Non-AUG Translation","volume":"104","author":"Cheng","year":"2019","journal-title":"Neuron"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"114768","DOI":"10.1016\/j.expneurol.2024.114768","article-title":"DDX3X overexpression decreases dipeptide repeat proteins in a mouse model of C9ORF72-ALS\/FTD","volume":"376","author":"Fu","year":"2024","journal-title":"Exp. Neurol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e105026","DOI":"10.15252\/embj.2020105026","article-title":"C9orf72 ALS\/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation","volume":"41","author":"Licata","year":"2022","journal-title":"EMBO J."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Seidel, M., Rajkumar, S., Steffke, C., Noeth, V., Agarwal, S., Roger, K., Lipecka, J., Ludolph, A., Guerrera, C.I., and Boeckers, T. (2023). Propranolol reduces the accumulation of cytotoxic aggregates in C9orf72-ALS\/FTD in vitro models. Curr. Res. Neurobiol., 5.","DOI":"10.1016\/j.crneur.2023.100105"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Premasiri, A.S., Gill, A.L., and Vieira, F.G. (2020). Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.569661"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Dane, T.L., Gill, A.L., Vieira, F.G., and Denton, K.R. (2023). Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity. Front. Cell Neurosci., 17.","DOI":"10.3389\/fncel.2023.1134090"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1093\/brain\/awz070","article-title":"Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity","volume":"142","author":"Xu","year":"2019","journal-title":"Brain"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"108925","DOI":"10.1016\/j.celrep.2021.108925","article-title":"UPF1 reduces C9orf72 HRE-induced neurotoxicity in the absence of nonsense-mediated decay dysfunction","volume":"34","author":"Zaepfel","year":"2021","journal-title":"Cell Rep."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1080\/15548627.2024.2358736","article-title":"Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects","volume":"20","author":"Renault","year":"2024","journal-title":"Autophagy"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"12432","DOI":"10.1021\/acs.jmedchem.3c00912","article-title":"Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve","volume":"66","author":"Li","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2998","DOI":"10.1093\/brain\/awae109","article-title":"Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: A randomized phase 2a clinical trial","volume":"147","author":"Babu","year":"2024","journal-title":"Brain"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"331","DOI":"10.24272\/j.issn.2095-8137.2022.356","article-title":"C9orf72 poly-GA proteins impair neuromuscular transmission","volume":"44","author":"Tu","year":"2023","journal-title":"Zool. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.cell.2008.10.002","article-title":"Lrp4 is a receptor for Agrin and forms a complex with MuSK","volume":"135","author":"Kim","year":"2008","journal-title":"Cell"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nrm1074","article-title":"New insights into the roles of agrin","volume":"4","author":"Bezakova","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Cicardi, M.E., Kankate, V., Sriramoji, S., Krishnamurthy, K., Markandaiah, S.S., Verdone, B.M., Girdhar, A., Nelson, A., Rivas, L.B., and Boehringer, A. (2024). The nuclear import receptor Kapbeta2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS\/FTD. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-06071-2"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Jafarinia, H., Van der Giessen, E., and Onck, P.R. (2022). Molecular basis of C9orf72 poly-PR interference with the beta-karyopherin family of nuclear transport receptors. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-25732-y"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"106579","DOI":"10.1016\/j.isci.2023.106579","article-title":"C9ORF72 suppresses JAK-STAT mediated inflammation","volume":"26","author":"Pang","year":"2023","journal-title":"iScience"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:25:05Z","timestamp":1760030705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":130,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094276"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094276","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,30]]}}}