Acknowledgement
This work was supported by Basic Science Research Program through the National Research Foundation of Korea (2022R1A4A2000703 and 2021R1A2C1003817) and the Korea Brain Research Institute Research Program (23-BR-03-02), funded by the Ministry of Science and ICT, Republic of Korea and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute and Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (HU21C0027)
References
- Ash, P.E., Bieniek, K.F., Gendron, T.F., Caulfield, T., Lin, W.L., Dejesus-Hernandez, M., van Blitterswijk, M.M., Jansen-West, K., Paul, J.W., 3rd, Rademakers, R., et al. (2013). Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron, 77, 639-646. https://doi.org/10.1016/j.neuron.2013.02.004
- Batra, R., and Lee, C.W. (2017). Mouse models of C9orf72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis/ frontotemporal dementia. Front. Cell. Neurosci. 11, 196. https://doi.org/10.3389/fncel.2017.00196
- Boeynaems, S., Bogaert, E., Michiels, E., Gijselinck, I., Sieben, A., Jovicic, A., De Baets, G., Scheveneels, W., Steyaert, J., Cuijt, I., et al. (2016). Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci. Rep. 6, 20877. https://doi.org/10.1038/srep20877
- Boivin, M., Pfister, V., Gaucherot, A., Ruffenach, F., Negroni, L., Sellier, C., and Charlet-Berguerand, N. (2020). Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders. EMBO J. 39, Article e100574. https://doi.org/10.15252/embj.2018100574
- Byrne, S., Heverin, M., Elamin, M., Bede, P., Lynch, C., Kenna, K., MacLaughlin, R., Walsh, C., Al Chalabi, A., and Hardiman, O. (2013). Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: a population-based case-control cohort study of familial and sporadic amyotrophic lateral sclerosis. Ann. Neurol. 74, 699-708. https://doi.org/10.1002/ana.23969
- Cho, J.H., Jo, M.G., Kim, E.S., Lee, N.Y., Kim, S.H., Chung, C.G., Park, J.H., and Lee, S.B. (2022). CBP-mediated acetylation of importin alpha mediates calcium-dependent nucleocytoplasmic transport of selective proteins in Drosophila neurons. Mol. Cells, 45, 855-867. https://doi.org/10.14348/molcells.2022.0104
- Chou, C.C., Zhang, Y., Umoh, M.E., Vaughan, S.W., Lorenzini, I., Liu, F., Sayegh, M., Donlin-Asp, P.G., Chen, Y.H., Duong, D.M., et al. (2018). TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat. Neurosci. 21, 228-239. https://doi.org/10.1038/s41593-017-0047-3
- Chung, C.G., Kwon, M.J., Jeon, K.H., Hyeon, D.Y., Han, M.H., Park, J.H., Cha, I.J., Cho, J.H., Kim, K., Rho, S., et al. (2017). Golgi outpost synthesis impaired by toxic polyglutamine proteins contributes to dendritic pathology in neurons. Cell Rep. 20, 356-369. https://doi.org/10.1016/j.celrep.2017.06.059
- Cunningham, K.M., Maulding, K., Ruan, K., Senturk, M., Grima, J.C., Sung, H., Zuo, Z., Song, H., Gao, J., Dubey, S., et al. (2020). TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS. Elife, 9. https://doi.org/10.7554/eLife.59419
- Dafinca, R., Scaber, J., Ababneh, N., Lalic, T., Weir, G., Christian, H., Vowles, J., Douglas, A.G., Fletcher-Jones, A., Browne, C., et al. (2016). 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. Stem Cells, 34, 2063-2078. https://doi.org/10.1002/stem.2388
- DeJesus-Hernandez, M., Mackenzie, I.R., Boeve, B.F., Boxer, A.L., Baker, M., Rutherford, N.J., Nicholson, A.M., Finch, N.A., Flynn, H., Adamson, J., et al. (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron, 72, 245-256. https://doi.org/10.1016/j.neuron.2011.09.011
- Devenney, E., Hornberger, M., Irish, M., Mioshi, E., Burrell, J., Tan, R., Kiernan, M.C., and Hodges, J.R. (2014). Frontotemporal dementia associated with the C9ORF72 mutation: a unique clinical profile. JAMA Neurol. 71, 331-339. https://doi.org/10.1001/jamaneurol.2013.6002
- Dubey, S.K., Maulding, K., Sung, H., and Lloyd, T.E. (2022). Nucleoporins are degraded via upregulation of ESCRT-III/Vps4 complex in Drosophila models of C9-ALS/FTD. Cell Rep. 40, Article 111379. https://doi.org/10.1016/j.celrep.2022.111379
- Gao, J., Mewborne, Q.T., Girdhar, A., Sheth, U., Coyne, A.N., Punathil, R., Kang, B.G., Dasovich, M., Veire, A., DeJesus Hernandez, M., et al. (2022). Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins. Sci. Transl. Med. 14, Article eabq3215. https://doi.org/10.1126/scitranslmed.abq3215
- Gasset-Rosa, F., Lu, S., Yu, H., Chen, C., Melamed, Z., Guo, L., Shorter, J., Da Cruz, S., and Cleveland, D.W. (2019). Cytoplasmic TDP43 de-mixing independent of stress granules drives inhibition of nuclear import, loss of nuclear TDP-43, and cell death. Neuron, 102, 339-357. https://doi.org/10.1016/j.neuron.2019.02.038
- Goodman, L.D., Prudencio, M., Kramer, N.J., Martinez-Ramirez, L.F., Srinivasan, A.R., Lan, M., Parisi, M.J., Zhu, Y., Chew, J., Cook, C.N., et al. (2019). Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD. Nat. Neurosci. 22, 863-874. https://doi.org/10.1038/s41593-019-0396-1
- Goodman, L.D., Prudencio, M., Srinivasan, A.R., Rifai, O.M., Lee, V.M., Petrucelli, L., and Bonini, N.M. (2019). eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS. Acta Neuropathol. Commun. 7, Article 62. https://doi.org/10.1186/s40478-019-0711-9
- Haeusler, A.R., Donnelly, C.J., and Rothstein, J.D. (2016). The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat. Rev. Neurosci. 17, 383-395. https://doi.org/10.1038/nrn.2016.38
- Kearse, M.G., Green, K.M., Krans, A., Rodriguez, C.M., Linsalata, A.E., Goldstrohm, A.C., and Todd, P.K. (2016). CGG repeat-associated nonAUG translation utilizes a Cap-dependent scanning mechanism of initiation to produce toxic proteins. Mol. Cell, 62, 314-322. https://doi.org/10.1016/j.molcel.2016.02.034
- Kim, E.S., Chung, C.G., Park, J.H., Ko, B.S., Park, S.S., Kim, Y.H., Cha, I.J., Kim, J., Ha, C.M., Kim, H.J., et al. (2021). C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent nuclear accumulation of Staufen in neurons. Hum. Mol. Genet. 30, 1084-1100. https://doi.org/10.1093/hmg/ddab089
- Kramer, N.J., Carlomagno, Y., Zhang, Y.J., Almeida, S., Cook, C.N., Gendron, T.F., Prudencio, M., Van Blitterswijk, M., Belzil, V., Couthouis, J., et al. (2016). Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science, 353, 708-712. https://doi.org/10.1126/science.aaf7791
- Kwiatkowski, T.J., Jr., Bosco, D.A., Leclerc, A.L., Tamrazian, E., Vanderburg, C.R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E.J., Munsat, T., et al. (2009). Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science, 323, 1205-1208. https://doi.org/10.1126/science.1166066
- Lee, J., Song, X., Hyun, B., Jeon, C.O., and Hyun, S. (2023). Drosophila gut immune pathway suppresses host development-promoting effects of acetic acid bacteria. Mol. Cells, 46, 637-653. https://doi.org/10.14348/molcells.2023.0141
- Lee, K.H., Zhang, P., Kim, H.J., Mitrea, D.M., Sarkar, M., Freibaum, B.D., Cika, J., Coughlin, M., Messing, J., Molliex, A., et al. (2016). C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell, 167, 774-788. https://doi.org/10.1016/j.cell.2016.10.002
- Lee, Y., Kim, J., Kim, H., Han, J.E., Kim, S., Kang, K.H., Kim, D., Kim, J.M., and Koh, H. (2022). Pyruvate dehydrogenase kinase protects dopaminergic neurons from oxidative stress in drosophila DJ-1 null mutants. Mol. Cells, 45, 454-464. https://doi.org/10.14348/molcells.2022.5002
- Lee, Y.B., Chen, H.J., Peres, J.N., Gomez-Deza, J., Attig, J., Stalekar, M., Troakes, C., Nishimura, A.L., Scotter, E.L., Vance, C., et al. (2013). Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178-1186. https://doi.org/10.1016/j.celrep.2013.10.049
- Li, C., Wu, B., Chen, S., Hao, K., Yang, J., Cao, H., Yang, S., Wu, Z.S., and Shen, Z. (2021). Structural requirement of G-quadruplex/aptamer-combined DNA macromolecule serving as efficient drug carrier for cancer-targeted drug delivery. Eur. J. Pharm. Biopharm. 159, 221-227. https://doi.org/10.1016/j.ejpb.2020.11.021
- Lin, M.J., Cheng, C.W., and Shen, C.K. (2011). Neuronal function and dysfunction of Drosophila dTDP. PLoS One, 6, Article e20371. https://doi.org/10.1371/journal.pone.0020371
- Liu, H., Lu, Y.N., Paul, T., Periz, G., Banco, M.T., Ferre-D'Amare, A.R., Rothstein, J.D., Hayes, L.R., Myong, S., and Wang, J. (2021). A helicase unwinds hexanucleotide repeat RNA G-quadruplexes and facilitates repeat-associated non-AUG translation. J. Am. Chem. Soc. 143, 7368-7379. https://doi.org/10.1021/jacs.1c00131
- Majounie, E., Renton, A.E., Mok, K., Dopper, E.G., Waite, A., Rollinson, S., Chio, A., Restagno, G., Nicolaou, N., Simon-Sanchez, J., et al. (2012). Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323-330. https://doi.org/10.1016/S1474-4422(12)70043-1
- McEachin, Z.T., Parameswaran, J., Raj, N., Bassell, G.J., and Jiang, J. (2020). RNA-mediated toxicity in C9orf72 ALS and FTD. Neurobiol. Dis. 145, Article 105055. https://doi.org/10.1016/j.nbd.2020.105055
- Mishra, S.K., Shankar, U., Jain, N., Sikri, K., Tyagi, J.S., Sharma, T.K., Mergny, J.L., and Kumar, A. (2019). Characterization of G-quadruplex motifs in espB, espK, and cyp51 genes of Mycobacterium tuberculosis as potential drug targets. Mol. Ther. Nucleic Acids, 16, 698-706. https://doi.org/10.1016/j.omtn.2019.04.022
- Mizielinska, S., Gronke, S., Niccoli, T., Ridler, C.E., Clayton, E.L., Devoy, A., Moens, T., Norona, F.E., Woollacott, I.O.C., Pietrzyk, J., et al. (2014). C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science, 345, 1192-1194. https://doi.org/10.1126/science.1256800
- Park, J.H., Chung, C.G., Park, S.S., Lee, D., Kim, K.M., Jeong, Y., Kim, E.S., Cho, J.H., Jeon, Y.M., Shen, C.J., et al. (2020). Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin alpha3. Elife, 9. https://doi.org/10.7554/eLife.60132
- Pradhan, R.N., Shrestha, B., and Lee, Y. (2023). Molecular basis of hexanoic acid taste in Drosophila melanogaster. Mol. Cells, 46, 451-460. https://doi.org/10.14348/molcells.2023.0035
- Rosen, D.R., Siddique, T., Patterson, D., Figlewicz, D.A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O'Regan, J.P., Deng, H.X., et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362, 59-62. https://doi.org/10.1038/362059a0
- Ryu, T.H., Subramanian, M., Yeom, E., and Yu, K. (2022). The promininlike gene expressed in a subset of dopaminergic neurons regulates locomotion in Drosophila. Mol. Cells, 45, 640-648. https://doi.org/10.14348/molcells.2022.0006
- Schmidt, J., Braggio, E., Kortuem, K.M., Egan, J.B., Zhu, Y.X., Xin, C.S., Tiedemann, R.E., Palmer, S.E., Garbitt, V.M., McCauley, D., et al. (2013). Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia, 27, 2357-2365. https://doi.org/10.1038/leu.2013.172
- Shatunov, A., Mok, K., Newhouse, S., Weale, M.E., Smith, B., Vance, C., Johnson, L., Veldink, J.H., van Es, M.A., van den Berg, L.H., et al. (2010). Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 9, 986-994. https://doi.org/10.1016/S1474-4422(10)70197-6
- Shi, Y., Lin, S., Staats, K.A., Li, Y., Chang, W.H., Hung, S.T., Hendricks, E., Linares, G.R., Wang, Y., Son, E.Y., et al. (2018). Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat. Med. 24, 313-325. https://doi.org/10.1038/nm.4490
- Solomon, D.A., Stepto, A., Au, W.H., Adachi, Y., Diaper, D.C., Hall, R., Rekhi, A., Boudi, A., Tziortzouda, P., Lee, Y.B., et al. (2018). A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-alpha mediates C9orf72-related neurodegeneration. Brain, 141, 2908-2924. https://doi.org/10.1093/brain/awy241
- Tran, H., Almeida, S., Moore, J., Gendron, T.F., Chalasani, U., Lu, Y., Du, X., Nickerson, J.A., Petrucelli, L., Weng, Z., et al. (2015). Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a Drosophila model of C9ORF72 FTD/ALS. Neuron, 87, 1207-1214. https://doi.org/10.1016/j.neuron.2015.09.015
- Tseng, Y.J., Sandwith, S.N., Green, K.M., Chambers, A.E., Krans, A., Raimer, H.M., Sharlow, M.E., Reisinger, M.A., Richardson, A.E., Routh, E.D., et al. (2021). The RNA helicase DHX36-G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat-associated translation. J. Biol. Chem. 297, Article 100914. https://doi.org/10.1016/j.jbc.2021.100914
- Van Daele, S.H., Moisse, M., van Vugt, J., Zwamborn, R.A.J., van der Spek, R., van Rheenen, W., Van Eijk, K., Kenna, K., Corcia, P., Vourc'h, P., et al. (2023). Genetic variability in sporadic amyotrophic lateral sclerosis. Brain, 146, 3760-3769. https://doi.org/10.1093/brain/awad120
- Vanneste, J., and Van Den Bosch, L. (2021). The role of nucleocytoplasmic transport defects in amyotrophic lateral sclerosis. Int. J. Mol. Sci. 22. https://doi.org/10.3390/ijms222212175
- Wang, Z.F., Ursu, A., Childs-Disney, J.L., Guertler, R., Yang, W.Y., Bernat, V., Rzuczek, S.G., Fuerst, R., Zhang, Y.J., Gendron, T.F., et al. (2019). The hairpin form of r(G(4)C(2))(exp) in c9ALS/FTD is repeat-associated non-ATG translated and a target for bioactive small molecules. Cell. Chem. Biol. 26, 179-190. https://doi.org/10.1016/j.chembiol.2018.10.018
- Wen, X., An, P., Li, H., Zhou, Z., Sun, Y., Wang, J., Ma, L., and Lu, B. (2020). Tau accumulation via reduced autophagy mediates GGGGCC repeat expansion-induced neurodegeneration in Drosophila model of ALS. Neurosci. Bull. 36, 1414-1428. https://doi.org/10.1007/s12264-020-00518-2
- Wen, X., Tan, W., Westergard, T., Krishnamurthy, K., Markandaiah, S.S., Shi, Y., Lin, S., Shneider, N.A., Monaghan, J., Pandey, U.B., et al. (2014). Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron, 84, 1213-1225. https://doi.org/10.1016/j.neuron.2014.12.010
- Xu, Z., Poidevin, M., Li, X., Li, Y., Shu, L., Nelson, D.L., Li, H., Hales, C.M., Gearing, M., Wingo, T.S., et al. (2013). Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 110, 7778-7783. https://doi.org/10.1073/pnas.1219643110
- Yuva-Aydemir, Y., Almeida, S., Krishnan, G., Gendron, T.F., and Gao, F.B. (2019). Transcription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD. Nat. Commun. 10, Article 5466. https://doi.org/10.1038/s41467-019-13477-8
- Zamiri, B., Reddy, K., Macgregor, R.B., Jr., and Pearson, C.E. (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, 4653-4659. https://doi.org/10.1074/jbc.C113.502336
- Zhang, K., Donnelly, C.J., Haeusler, A.R., Grima, J.C., Machamer, J.B., Steinwald, P., Daley, E.L., Miller, S.J., Cunningham, K.M., Vidensky, A., et al. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature, 525, 56-61. https://doi.org/10.1038/nature14973
- Zu, T., Liu, Y., Banez-Coronel, M., Reid, T., Pletnikova, O., Lewis, J., Miller, T.M., Harms, M.B., Falchook, A.E., Subramony, S.H., et al. (2013). RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl. Acad. Sci. U.S.A. 110, E4968-E4977. https://doi.org/10.1073/pnas.1315438110