Browse > Article
http://dx.doi.org/10.14348/molcells.2020.0130

C9orf72-Associated Arginine-Rich Dipeptide Repeat Proteins Reduce the Number of Golgi Outposts and Dendritic Branches in Drosophila Neurons  

Park, Jeong Hyang (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Chung, Chang Geon (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Seo, Jinsoo (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Lee, Byung-Hoon (Protein Dynamics-Based Proteotoxicity Control Laboratory, Basic Research Lab, DGIST)
Lee, Young-Sam (Protein Dynamics-Based Proteotoxicity Control Laboratory, Basic Research Lab, DGIST)
Kweon, Jung Hyun (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Lee, Sung Bae (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Publication Information
Molecules and Cells / v.43, no.9, 2020 , pp. 821-830 More about this Journal
Abstract
Altered dendritic morphology is frequently observed in various neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the cellular and molecular basis underlying these pathogenic dendritic abnormalities remains largely unclear. In this study, we investigated dendritic morphological defects caused by dipeptide repeat protein (DPR) toxicity associated with G4C2 expansion mutation of C9orf72 (the leading genetic cause of ALS and FTD) in Drosophila neurons and characterized the underlying pathogenic mechanisms. Among the five DPRs produced by repeat-associated non-ATG translation of G4C2 repeats, we found that arginine-rich DPRs (PR and GR) led to the most significant reduction in dendritic branches and plasma membrane (PM) supply in Class IV dendritic arborization (C4 da) neurons. Furthermore, expression of PR and GR reduced the number of Golgi outposts (GOPs) in dendrites. In Drosophila brains, expression of PR, but not GR, led to a significant reduction in the mRNA level of CrebA, a transcription factor regulating the formation of GOPs. Overexpressing CrebA in PR-expressing C4 da neurons mitigated PM supply defects and restored the number of GOPs, but the number of dendritic branches remained unchanged, suggesting that other molecules besides CrebA may be involved in dendritic branching. Taken together, our results provide valuable insight into the understanding of dendritic pathology associated with C9-ALS/FTD.
Keywords
amyotrophic lateral sclerosis; C9orf72; CrebA; dendrites; Golgi outposts;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 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, e100574.
2 Burk, K. and Pasterkamp, R.J. (2019). Disrupted neuronal trafficking in amyotrophic lateral sclerosis. Acta Neuropathol. 137, 859-877.   DOI
3 Caracci, M.O., Fuentealba, L.M., and Marzolo, M.P. (2019). Golgi complex dynamics and its implication in prevalent neurological disorders. Front. Cell Dev. Biol. 7, 75.   DOI
4 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.   DOI
5 Clayton, E.L., Milioto, C., Muralidharan, B., Norona, F.E., Edgar, J.R., Soriano, A., Jafar-Nejad, P., Rigo, F., Collinge, J., and Isaacs, A.M. (2018). Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown. Brain 141, 3428-3442.   DOI
6 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.   DOI
7 Farg, M.A., Sundaramoorthy, V., Sultana, J.M., Yang, S., Atkinson, R.A., Levina, V., Halloran, M.A., Gleeson, P.A., Blair, I.P., Soo, K.Y., et al. (2014). C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum. Mol. Genet. 23, 3579-3595.   DOI
8 Ferrer, I. (1999). Neurons and their dendrites in frontotemporal dementia. Dement. Geriatr. Cogn. Disord. 10 Suppl 1, 55-60.   DOI
9 Fischer, L.R. and Glass, J.D. (2007). Axonal degeneration in motor neuron disease. Neurodegener. Dis. 4, 431-442.   DOI
10 Fox, R.M., Hanlon, C.D., and Andrew, D.J. (2010). The CrebA/Creb3-like transcription factors are major and direct regulators of secretory capacity. J. Cell Biol. 191, 479-492.   DOI
11 Freibaum, B.D. and Taylor, J.P. (2017). The Role of dipeptide repeats in C9ORF72-related ALS-FTD. Front. Mol. Neurosci. 10, 35.
12 Gonatas, N.K., Stieber, A., and Gonatas, J.O. (2006). Fragmentation of the Golgi apparatus in neurodegenerative diseases and cell death. J. Neurol. Sci. 246, 21-30.   DOI
13 Goodier, J.L., Soares, A.O., Pereira, G.C., DeVine, L.R., Sanchez, L., Cole, R.N., and García-Pérez, J.L. (2020). C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease. Acta Neuropathol. Commun. 8, 110.   DOI
14 Hayes, L.R., Duan, L., Bowen, K., Kalab, P., and Rothstein, J.D. (2020). C9orf72 arginine-rich dipeptide repeat proteins disrupt karyopherinmediated nuclear import. eLife 9, e51685.   DOI
15 Herzog, J.J., Deshpande, M., Shapiro, L., Rodal, A.A., and Paradis, S. (2017). TDP-43 misexpression causes defects in dendritic growth. Sci. Rep. 7, 15656.   DOI
16 Horton, A.C., Racz, B., Monson, E.E., Lin, A.L., Weinberg, R.J., and Ehlers, M.D. (2005). Polarized secretory trafficking directs cargo for asymmetric dendrite growth and morphogenesis. Neuron 48, 757-771.   DOI
17 Ikeda, Y., Ohta, Y., Kobayashi, H., Okamoto, M., Takamatsu, K., Ota, T., Manabe, Y., Okamoto, K., Koizumi, A., and Abe, K. (2012). Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan). Neurology 79, 333-341.   DOI
18 Fu, L., Gao, Y.S., and Sztul, E. (2005). Transcriptional repression and cell death induced by nuclear aggregates of non-polyglutamine rotein. Neurobiol. Dis. 20, 656-665.   DOI
19 Iyer, S.C., Ramachandran Iyer, E.P., Meduri, R., Rubaharan, M., Kuntimaddi, A., Karamsetty, M., and Cox, D.N. (2013). Cut, via CrebA, transcriptionally regulates the COPII secretory pathway to direct dendrite development in Drosophila. J. Cell Sci. 126, 4732-4745.   DOI
20 Jan, Y.N. and Jan, L.Y. (2010). Branching out: mechanisms of dendritic arborization. Nat. Rev. Neurosci. 11, 316-328.   DOI
21 Karpati, G., Carpenter, S., and Durham, H. (1988). A hypothesis for the pathogenesis of amyotrophic lateral sclerosis. Rev. Neurol. (Paris) 144, 672-675.
22 Kobayashi, H., Abe, K., Matsuura, T., Ikeda, Y., Hitomi, T., Akechi, Y., Habu, T., Liu, W., Okuda, H., and Koizumi, A. (2011). Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am. J. Hum. Genet. 89, 121-130.   DOI
23 Kulkarni, V.A. and Firestein, B.L. (2012). The dendritic tree and brain disorders. Mol. Cell. Neurosci. 50, 10-20.   DOI
24 Kweon, J.H., Kim, S., and Lee, S.B. (2017). The cellular basis of dendrite pathology in neurodegenerative diseases. BMB Rep. 50, 5-11.   DOI
25 Kwon, I., Xiang, S., Kato, M., Wu, L., Theodoropoulos, P., Wang, T., Kim, J., Yun, J., Xie, Y., and McKnight, S.L. (2014). Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345, 1139-1145.   DOI
26 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.   DOI
27 Kwon, M.J., Han, M.H., Bagley, J.A., Hyeon, D.Y., Ko, B.S., Lee, Y.M., Cha, I.J., Kim, S.Y., Kim, D.Y., Kim, H.M., et al. (2018). Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects. Proc. Natl. Acad. Sci. U. S. A. 115, E10748-E10757.
28 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.e17.   DOI
29 Lee, S.B., Bagley, J.A., Lee, H.Y., Jan, L.Y., and Jan, Y.N. (2011). Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila. Proc. Natl. Acad. Sci. U. S. A. 108, 16795-16800.   DOI
30 Lin, C.H., Li, H., Lee, Y.N., Cheng, Y.J., Wu, R.M., and Chien, C.T. (2015). Lrrk regulates the dynamic profile of dendritic Golgi outposts through the golgin Lava lamp. J. Cell Biol. 210, 471-483.   DOI
31 Ling, S.C., Polymenidou, M., and Cleveland, D.W. (2013). Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79, 416-438.   DOI
32 Mao, D., Lin, G., Tepe, B., Zuo, Z., Tan, K.L., Senturk, M., Zhang, S., Arenkiel, B.R., Sardiello, M., and Bellen, H.J. (2019). VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway. Autophagy 15, 1214-1233.   DOI
33 Nakano, I. and Hirano, A. (1987). Atrophic cell processes of large motor neurons in the anterior horn in amyotrophic lateral sclerosis: observation with silver impregnation method. J. Neuropathol. Exp. Neurol. 46, 40-49.   DOI
34 McCampbell, A., Taylor, J.P., Taye, A.A., Robitschek, J., Li, M., Walcott, J., Merry, D., Chai, Y., Paulson, H., Sobue, G., et al. (2000). CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet. 9, 2197-2202.   DOI
35 McEachin, Z.T., Gendron, T.F., Raj, N., Garcia-Murias, M., Banerjee, A., Purcell, R.H., Ward, P.J., Todd, T.W., Merritt-Garza, M.E., Jansen-West, K., et al. (2020). Chimeric peptide species contribute to divergent dipeptide repeat pathology in c9ALS/FTD and SCA36. Neuron 107, 292-305.e6.   DOI
36 Murthy, M., Ranjan, R., Denef, N., Higashi, M.E., Schupbach, T., and Schwarz, T.L. (2005). Sec6 mutations and the Drosophila exocyst complex. J. Cell Sci. 118, 1139-1150.   DOI
37 Nucifora, F.C., Jr., Sasaki, M., Peters, M.F., Huang, H., Cooper, J.K., Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J., Dawson, V.L., et al. (2001). Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291, 2423-2428.   DOI
38 Ori-McKenney, K.M., Jan, L.Y., and Jan, Y.N. (2012). Golgi outposts shape dendrite morphology by functioning as sites of acentrosomal microtubule nucleation in neurons. Neuron 76, 921-930.   DOI
39 Pfenninger, K.H. (2009). Plasma membrane expansion: a neuron's Herculean task. Nat. Rev. Neurosci. 10, 251-261.   DOI
40 Renton, A.E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J.R., Schymick, J.C., Laaksovirta, H., van Swieten, J.C., Myllykangas, L., et al. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268.   DOI
41 Steffan, J.S., Kazantsev, A., Spasic-Boskovic, O., Greenwald, M., Zhu, Y.Z., Gohler, H., Wanker, E.E., Bates, G.P., Housman, D.E., and Thompson, L.M. (2000). The Huntington's disease protein interacts with p53 and CREBbinding protein and represses transcription. Proc. Natl. Acad. Sci. U. S. A. 97, 6763-6768.   DOI
42 Rudich, P., Snoznik, C., Watkins, S.C., Monaghan, J., Pandey, U.B., and Lamitina, S.T. (2017). Nuclear localized C9orf72-associated argininecontaining dipeptides exhibit age-dependent toxicity in C. elegans. Hum. Mol. Genet. 26, 4916-4928.   DOI
43 Saberi, S., Stauffer, J.E., Schulte, D.J., and Ravits, J. (2015). Neuropathology of amyotrophic lateral sclerosis and its variants. Neurol. Clin. 33, 855-876.   DOI
44 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.   DOI
45 Sun, Y., Eshov, A., Zhou, J., Isiktas, A.U., and Guo, J.U. (2020). C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression. Nat. Commun. 11, 3354.   DOI
46 Swinnen, B., Robberecht, W., and Van Den Bosch, L. (2020). RNA toxicity in non-coding repeat expansion disorders. EMBO J. 39, e101112.
47 Todd, T.W., McEachin, Z.T., Chew, J., Burch, A.R., Jansen-West, K., Tong, J., Yue, M., Song, Y., Castanedes-Casey, M., Kurti, A., et al. (2020). Hexanucleotide repeat expansions in c9FTD/ALS and SCA36 confer selective patterns of neurodegeneration in vivo. Cell Rep. 31, 107616.   DOI
48 Takeda, T., Uchihara, T., Nakayama, Y., Nakamura, A., Sasaki, S., Kakei, S., Uchiyama, S., Duyckaerts, C., and Yoshida, M. (2014). Dendritic retraction, but not atrophy, is consistent in amyotrophic lateral sclerosis-comparison between Onuf's neurons and other sacral motor neurons. Acta Neuropathol. Commun. 2, 11.   DOI
49 Taylor, J.P., Brown, R.H., Jr., and Cleveland, D.W. (2016). Decoding ALS: from genes to mechanism. Nature 539, 197-206.   DOI
50 Tibshirani, M., Zhao, B., Gentil, B.J., Minotti, S., Marques, C., Keith, J., Rogaeva, E., Zinman, L., Rouaux, C., Robertson, J., et al. (2017). Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis. Hum. Mol. Genet. 26, 4142-4152.   DOI
51 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.   DOI
52 Xu, F., Kula-Eversole, E., Iwanaszko, M., Lim, C., and Allada, R. (2019). Ataxin2 functions via CrebA to mediate Huntingtin toxicity in circadian clock neurons. PLoS Genet. 15, e1008356.   DOI
53 Zhu, Q., Jiang, J., Gendron, T.F., McAlonis-Downes, M., Jiang, L., Taylor, A., Diaz Garcia, S., Ghosh Dastidar, S., Rodriguez, M.J., King, P., et al. (2020). Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTDcausing repeat expansion in C9orf72. Nat. Neurosci. 23, 615-624   DOI
54 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.   DOI
55 Ye, B., Zhang, Y., Song, W., Younger, S.H., Jan, L.Y., and Jan, Y.N. (2007). Growing dendrites and axons differ in their reliance on the secretory pathway. Cell 130, 717-729.   DOI
56 Yin, S., Lopez-Gonzalez, R., Kunz, R.C., Gangopadhyay, J., Borufka, C., Gygi, S.P., Gao, F.B., and Reed, R. (2017). Evidence that C9ORF72 dipeptide repeat proteins associate with U2 snRNP to cause mis-splicing in ALS/FTD patients. Cell Rep. 19, 2244-2256.   DOI