Browse > Article
http://dx.doi.org/10.14348/molcells.2020.0158

Ataxin-2 Dysregulation Triggers a Compensatory Fragile X Mental Retardation Protein Decrease in Drosophila C4da Neurons  

Cha, In Jun (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Lee, Davin (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Park, Sung Soon (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))
Kim, Seung Yeon (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Jo, Min Gu (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Kim, Seung Yeol (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)
Lee, Sung Bae (Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Publication Information
Molecules and Cells / v.43, no.10, 2020 , pp. 870-879 More about this Journal
Abstract
Dendrites require precise and timely delivery of protein substrates to distal areas to ensure the correct morphology and function of neurons. Many of these protein substrates are supplied in the form of ribonucleoprotein (RNP) complex consisting of RNA-binding proteins (RBPs) and mRNAs, which are subsequently translated in distal dendritic areas. It remains elusive, however, whether key RBPs supply mRNA according to local demands individually or in a coordinated manner. In this study, we investigated how Drosophila sensory neurons respond to the dysregulation of a disease-associated RBP, Ataxin-2 (ATX2), which leads to dendritic defects. We found that ATX2 plays a crucial role in spacing dendritic branches for the optimal dendritic receptive fields in Drosophila class IV dendritic arborization (C4da) neurons, where both expression level and subcellular location of ATX2 contribute significantly to this effect. We showed that translational upregulation through the expression of eukaryotic translation initiation factor 4E (eIF4E) further enhanced the ATX2-induced dendritic phenotypes. Additionally, we found that the expression level of another disease-associated RBP, fragile X mental retardation protein (FMRP), decreased in both cell bodies and dendrites when neurons were faced with aberrant upregulation of ATX2. Finally, we revealed that the PAM2 motif of ATX2, which mediates its interaction with poly(A)-binding protein (PABP), is potentially necessary for the decrease of FMRP in certain neuronal stress conditions. Collectively, our data suggest that dysregulation of RBPs triggers a compensatory regulation of other functionally-overlapping RBPs to minimize RBP dysregulation-associated aberrations that hinder neuronal homeostasis in dendrites.
Keywords
Ataxin-2; dendrite; fragile X mental retardation protein; mRNA supply; RNA-binding protein;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Ashley, C.T., Jr., Wilkinson, K.D., Reines, D., and Warren, S.T. (1993). FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262, 563-566.   DOI
2 Bakthavachalu, B., Huelsmeier, J., Sudhakaran, I.P., Hillebrand, J., Singh, A., Petrauskas, A., Thiagarajan, D., Sankaranarayanan, M., Mizoue, L., Anderson, E.N., et al. (2018). RNP-granule assembly via Ataxin-2 disordered domains is required for long-term memory and neurodegeneration. Neuron 98, 754-766.e4.   DOI
3 Conlon, E.G. and Manley, J.L. (2017). RNA-binding proteins in neurodegeneration: mechanisms in aggregate. Genes Dev. 31, 1509-1528.   DOI
4 Ding, D., Li, K., Wang, C., Chen, Z., Long, Z., Peng, Y., Zhou, X., Peng, H., Qiu, R., Xia, K., et al. (2016). ATXN2 polymorphism modulates age at onset in Machado-Joseph disease. Brain 139, e59.
5 Eberhart, D.E., Malter, H.E., Feng, Y., and Warren, S.T. (1996). The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum. Mol. Genet. 5, 1083-1091.   DOI
6 Elden, A.C., Kim, H.J., Hart, M.P., Chen-Plotkin, A.S., Johnson, B.S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M.M., et al. (2010). Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069-1075.   DOI
7 Gingras, A.C., Raught, B., and Sonenberg, N. (1999). eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913-963.   DOI
8 Gruner, S., Peter, D., Weber, R., Wohlbold, L., Chung, M.Y., Weichenrieder, O., Valkov, E., Igreja, C., and Izaurralde, E. (2016). The structures of eIF4EeIF4G complexes reveal an extended interface to regulate translation initiation. Mol. Cell 64, 467-479.   DOI
9 Hanson, K.A., Kim, S.H., and Tibbetts, R.S. (2012). RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond. Wiley Interdiscip. Rev. RNA 3, 265-285.
10 Hentze, M.W., Castello, A., Schwarzl, T., and Preiss, T. (2018). A brave new world of RNA-binding proteins. Nat. Rev. Mol. Cell Biol. 19, 327-341.   DOI
11 Heyburn, L. and Moussa, C.E. (2017). TDP-43 in the spectrum of MNDFTLD pathologies. Mol. Cell. Neurosci. 83, 46-54.   DOI
12 Kishore, S., Luber, S., and Zavolan, M. (2010). Deciphering the role of RNAbinding proteins in the post-transcriptional control of gene expression. Brief. Funct. Genomics 9, 391-404.   DOI
13 Lastres-Becker, I., Nonis, D., Eich, F., Klinkenberg, M., Gorospe, M., Kotter, P., Klein, F.A., Kedersha, N., and Auburger, G. (2016). Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation. Biochim. Biophys. Acta 1862, 1558-1569.   DOI
14 Lee, A., Li, W., Xu, K., Bogert, B.A., Su, K., and Gao, F.B. (2003). Control of dendritic development by the Drosophila fragile X-related gene involves the small GTPase Rac1. Development 130, 5543-5552.   DOI
15 Lee, D., Lee, Y.I., Lee, Y.S., and Lee, S.B. (2020). The mechanisms of nuclear proteotoxicity in polyglutamine spinocerebellar ataxias. Front. Neurosci. 14, 489.   DOI
16 Lessing, D. and Bonini, N.M. (2008). Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila. PLoS Biol. 6, e29.   DOI
17 Lim, C. and Allada, R. (2013). ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila. Science 340, 875-879.   DOI
18 Neumann, M., Sampathu, D.M., Kwong, L.K., Truax, A.C., Micsenyi, M.C., Chou, T.T., Bruce, J., Schuck, T., Grossman, M., Clark, C.M., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133.   DOI
19 McCann, C., Holohan, E.E., Das, S., Dervan, A., Larkin, A., Lee, J.A., Rodrigues, V., Parker, R., and Ramaswami, M. (2011). The Ataxin-2 protein is required for microRNA function and synapse-specific long-term olfactory habituation. Proc. Natl. Acad. Sci. U. S. A. 108, E655-E662.   DOI
20 Nalavadi, V.C., Muddashetty, R.S., Gross, C., and Bassell, G.J. (2012). Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation. J. Neurosci. 32, 2582-2587.   DOI
21 Nkiliza, A., Mutez, E., Simonin, C., Lepretre, F., Duflot, A., Figeac, M., Villenet, C., Semaille, P., Comptdaer, T., Genet, A., et al. (2016). RNAbinding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease. Neurobiol. Dis. 96, 312-322.   DOI
22 Nonhoff, U., Ralser, M., Welzel, F., Piccini, I., Balzereit, D., Yaspo, M.L., Lehrach, H., and Krobitsch, S. (2007). Ataxin-2 interacts with the DEAD/ H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol. Biol. Cell 18, 1385-1396.   DOI
23 Park, J.H., Chung, C.G., Seo, J., Lee, B.H., Lee, Y.S., Kweon, J.H., and Lee, S.B. (2020). C9orf72-associated arginine-rich dipeptide repeat proteins reduce the number of Golgi outposts and dendritic branches in Drosophila neurons. Mol. Cells 43, 821-830.   DOI
24 Paulson, H.L., Shakkottai, V.G., Clark, H.B., and Orr, H.T. (2017). Polyglutamine spinocerebellar ataxias - from genes to potential treatments. Nat. Rev. Neurosci. 18, 613-626.   DOI
25 Satterfield, T.F., Jackson, S.M., and Pallanck, L.J. (2002). A Drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation. Genetics 162, 1687-1702.   DOI
26 Protter, D.S.W. and Parker, R. (2016). Principles and properties of stress granules. Trends Cell Biol. 26, 668-679.   DOI
27 Ravanidis, S., Kattan, F.G., and Doxakis, E. (2018). Unraveling the pathways to neuronal homeostasis and disease: mechanistic insights into the role of RNA-binding proteins and associated factors. Int. J. Mol. Sci. 19, 2280.   DOI
28 Romano, M. and Buratti, E. (2013). Targeting RNA binding proteins involved in neurodegeneration. J. Biomol. Screen. 18, 967-983.   DOI
29 Siomi, H., Siomi, M.C., Nussbaum, R.L., and Dreyfuss, G. (1993). The protein product of the fragile X gene, FMR1, has characteristics of an RNAbinding protein. Cell 74, 291-298.   DOI
30 Sudhakaran, I.P., Hillebrand, J., Dervan, A., Das, S., Holohan, E.E., Hulsmeier, J., Sarov, M., Parker, R., VijayRaghavan, K., and Ramaswami, M. (2014). FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control. Proc. Natl. Acad. Sci. U. S. A. 111, E99-E108.   DOI
31 Van Damme, P., Veldink, J.H., van Blitterswijk, M., Corveleyn, A., van Vught, P.W., Thijs, V., Dubois, B., Matthijs, G., van den Berg, L.H., and Robberecht, W. (2011). Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology 76, 2066-2072.   DOI
32 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
33 Zhang, Y., Ling, J., Yuan, C., Dubruille, R., and Emery, P. (2013). A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science 340, 879-882.   DOI
34 Yokoshi, M., Li, Q., Yamamoto, M., Okada, H., Suzuki, Y., and Kawahara, Y. (2014). Direct binding of Ataxin-2 to distinct elements in 3' UTRs promotes mRNA stability and protein expression. Mol. Cell 55, 186-198.   DOI