Abstract
Local translation in neuronal dendrites is an important basis for synaptic plasticity that underlies long-term memory formation. RNA granules, which are dynamic condensates consisting of mRNAs, ribosomes, and RNA-binding proteins, are essential for transporting mRNAs to dendrites and regulating local dendritic translation. Through coordinating and modulating the translation of specific mRNAs, these granules enable neurons to refine synaptic connections in response to synaptic inputs at the appropriate temporal and spatial scales. Recent studies have revealed that RNA granules form through liquid–liquid phase separation (LLPS), which allows them to adapt to changes in synaptic inputs and switch between different translational states. However, dysregulation of RNA granule dynamics, particularly the formation of aberrant aggregates, has been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Thus, RNA granules play a pivotal role in maintaining synaptic plasticity and cognitive function in healthy neurons, while their dysregulation may contribute to neurodegeneration.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ainsley JA, Drane L, Jacobs J, Kittelberger KA, Reijmers LG (2014) Functionally diverse dendritic mRNAs rapidly associate with ribosomes following a novel experience. Nat Commun 5:4510. https://doi.org/10.1038/ncomms5510
Baker KB, Wray SP, Ritter R, Mason S, Lanthorn TH, Savelieva KV (2010) Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments. Genes Brain Behav 9:562–574. https://doi.org/10.1111/j.1601-183X.2010.00585.x
Berger-Sweeney J, Zearfoss NR, Richter JD (2006) Reduced extinction of hippocampal-dependent memories in CPEB knockout mice. Learn Mem 13:4–7. https://doi.org/10.1101/lm.73706
Bowden HA, Dormann D (2016) Altered mRNP granule dynamics in FTLD pathogenesis. J Neurochem 138:112–133. https://doi.org/10.1111/jnc.13601
Buxbaum AR, Wu B, Singer RH (2014) Single β-actin mRNA detection in neurons reveals a mechanism for regulating its translatability. Science 343:419–422. https://doi.org/10.1126/science.1242939
Cajigas IJ, Tushev G, Will TJ, tom Dieck S, Fuerst N, Schuman EM (2012) The local transcriptome in the synaptic neuropil revealed by deep sequencing and high-resolution imaging. Neuron 74:453–466. https://doi.org/10.1016/j.neuron.2012.02.036
Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N (2009) Translational control of long-lasting synaptic plasticity and memory. Neuron 61:10–26. https://doi.org/10.1016/j.neuron.2008.10.055
Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–261. https://doi.org/10.1016/j.cell.2011.06.013
D'Hooge R, Nagels G, Franck F, Bakker CE, Reyniers E, Storm K, Kooy RF, Oostra BA, Willems PJ, De Deyn PP (1997) Mildly impaired water maze performance in male Fmr1 knockout mice. Neuroscience 76:367–376. https://doi.org/10.1016/s0306-4522(96)00224-2
Dictenberg JB, Swanger SA, Antar LN, Singer RH, Bassell GJ (2008) A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev Cell 14:926–939. https://doi.org/10.1016/j.devcel.2008.04.003
Ding Q, Sethna F, Wang H (2014) Behavioral analysis of male and female Fmr1 knockout mice on C57BL/6 background. Behav Brain Res 271:72–78. https://doi.org/10.1016/j.bbr.2014.05.046
El Fatimy R, Davidovic L, Tremblay S, Jaglin X, Dury A, Robert C, De Koninck P, Khandjian EW (2016) Tracking the fragile X mental retardation protein in a highly ordered neuronal ribonucleoparticles population: a link between stalled polyribosomes and RNA granules. PLoS Genet 12:e1006192. https://doi.org/10.1371/journal.pgen.1006192
Fritzsche R, Karra D, Bennett KL, Ang FY, Heraud-Farlow JE, Tolino M, Doyle M, Bauer KE, Thomas S, Planyavsky M, Arn E, Bakosova A, Jungwirth K, Hörmann A, Palfi Z, Sandholzer J, Schwarz M, Macchi P, Colinge J, Superti-Furga G, Kiebler MA (2013) Interactome of two diverse RNA granules links mRNA localization to translational repression in neurons. Cell Rep 5:1749–1762. https://doi.org/10.1016/j.celrep.2013.11.023
Gelon PA, Dutchak PA, Sephton CF (2022) Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease. Front Mol Neurosci 15:1000183. https://doi.org/10.3389/fnmol.2022.1000183
Guillén-Boixet J, Kopach A, Holehouse AS, Wittmann S, Jahnel M, Schlüßler R, Kim K, Trussina IREA, Wang J, Mateju D, Poser I, Maharana S, Ruer-Gruß M, Richter D, Zhang X, Chang YT, Guck J, Honigmann A, Mahamid J, Hyman AA, Pappu RV, Alberti S, Franzmann TM (2020) RNA-induced conformational switching and clustering of G3BP drive stress granule assembly by condensation. Cell 181:346–361.e17. https://doi.org/10.1016/j.cell.2020.03.049
Hallegger M, Chakrabarti AM, Lee FCY, Lee BL, Amalietti AG, Odeh HM, Copley KE, Rubien JD, Portz B, Kuret K, Huppertz I, Rau F, Patani R, Fawzi NL, Shorter J, Luscombe NM, Ule J (2021) TDP-43 condensation properties specify its RNA-binding and regulatory repertoire. Cell 184:4680–4696.e22. https://doi.org/10.1016/j.cell.2021.07.018
Harrison AF, Shorter J (2017) RNA-binding proteins with prion-like domains in health and disease. Biochem J 474:1417–1438. https://doi.org/10.1042/BCJ20160499
Heraud-Farlow JE, Sharangdhar T, Li X, Pfeifer P, Tauber S, Orozco D, Hörmann A, Thomas S, Bakosova A, Farlow AR, Edbauer D, Lipshitz HD, Morris QD, Bilban M, Doyle M, Kiebler MA (2013) Staufen 2 regulates neuronal target RNAs. Cell Rep 5:1511–1518. https://doi.org/10.1016/j.celrep.2013.11.039
Hofweber M, Dormann D (2019) Friend or foe-post-translational modifications as regulators of phase separation and RNP granule dynamics. J Biol Chem 294:7137–7150. https://doi.org/10.1074/jbc.TM118.001189
Hofweber M, Hutten S, Bourgeois B, Spreitzer E, Niedner-Boblenz A, Schifferer M, Ruepp MD, Simons M, Niessing D, Madl T, Dormann D (2018) Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173:706–719.e13. https://doi.org/10.1016/j.cell.2018.03.004
Holt CE, Martin KC, Schuman EM (2019) Local translation in neurons: visualization and function. Nat Struct Mol Biol 26:557–566. https://doi.org/10.1038/s41594-019-0263-5
Honda M, Oki S, Kimura R, Harada A, Maehara K, Tanaka K, Meno C, Ohkawa Y (2021) High-depth spatial transcriptome analysis by photo-isolation chemistry. Nat Commun 12:4416. https://doi.org/10.1038/s41467-021-24691-8
Hong K, Song D, Jung Y (2020) Behavior control of membrane-less protein liquid condensates with metal ion-induced phase separation. Nat Commun 11:5554. https://doi.org/10.1038/s41467-020-19391-8
Huynh DP, Maalouf M, Silva AJ, Schweizer FE, Pulst SM (2009) Dissociated fear and spatial learning in mice with deficiency of ataxin-2. PLoS One 4:e 6235. https://doi.org/10.1371/journal.pone.0006235
Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R (2016) ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164:487–498. https://doi.org/10.1016/j.cell.2015.12.038
Kanai Y, Dohmae N, Hirokawa N (2004) Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43:513–525. https://doi.org/10.1016/j.neuron.2004.07.022
Kang H, Schuman EM (1996) A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273:1402–1406. https://doi.org/10.1126/science.273.5280.1402
Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, Grishin NV, Frantz DE, Schneider JW, Chen S, Li L, Sawaya MR, Eisenberg D, Tycko R, McKnight SL (2012) Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753–767. https://doi.org/10.1016/j.cell.2012.04.017
Khong A, Matheny T, Jain S, Mitchell SF, Wheeler JR, Parker R (2017) The stress granule transcriptome reveals principles of mRNA accumulation in stress granules. Mol Cell 68:808–820.e5. https://doi.org/10.1016/j.molcel.2017.10.015
Kiebler MA, Bassell GJ (2006) Neuronal RNA granules: movers and makers. Neuron 51:685–690. https://doi.org/10.1016/j.neuron.2006.08.021
Kiebler MA, Hemraj I, Verkade P, Köhrmann M, Fortes P, Marión RM, OrtÃn J, Dotti CG (1999) The mammalian staufen protein localizes to the somatodendritic domain of cultured hippocampal neurons: implications for its involvement in mRNA transport. J Neurosci 19:288–297. https://doi.org/10.1523/JNEUROSCI.19-01-00288.1999
Kim TH, Tsang B, Vernon RM, Sonenberg N, Kay LE, Forman-Kay JD (2019) Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation. Science 365:825–829. https://doi.org/10.1126/science.aax4240
Klann E, Dever TE (2004) Biochemical mechanisms for translational regulation in synaptic plasticity. Nat Rev Neurosci 5:931–942. https://doi.org/10.1038/nrn1557
Knowles RB, Sabry JH, Martone ME, Deerinck TJ, Ellisman MH, Bassell GJ, Kosik KS (1996) Translocation of RNA granules in living neurons. J Neurosci 16:7812–7820. https://doi.org/10.1523/JNEUROSCI.16-24-07812.1996
Krainer G, Welsh TJ, Joseph JA, Espinosa JR, Wittmann S, de Csilléry E, Sridhar A, Toprakcioglu Z, Gudiškytė G, Czekalska MA, Arter WE, Guillén-Boixet J, Franzmann TM, Qamar S, George-Hyslop PS, Hyman AA, Collepardo-Guevara R, Alberti S, Knowles TPJ (2021) Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions. Nat Commun 12:1085. https://doi.org/10.1038/s41467-021-21181-9
Krichevsky AM, Kosik KS (2001) Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32:683–696. https://doi.org/10.1016/s0896-6273(01)00508-6
Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19:R46–R64. https://doi.org/10.1093/hmg/ddq137
Langdon EM, Qiu Y, Ghanbari Niaki A, McLaughlin GA, Weidmann CA, Gerbich TM, Smith JA, Crutchley JM, Termini CM, Weeks KM, Myong S, Gladfelter AS (2018) mRNA structure determines specificity of a poly Q-driven phase separation. Science 360:922–927. https://doi.org/10.1126/science.aar7432
Langille JJ, Ginzberg K, Sossin WS (2019) Polysomes identified by live imaging of nascent peptides are stalled in hippocampal and cortical neurites. Learn Mem 26:351–362. https://doi.org/10.1101/lm.049965.119
Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. https://doi.org/10.1016/j.neuron.2013.07.033
Maharana S, Wang J, Papadopoulos DK, Richter D, Pozniakovsky A, Poser I, Bickle M, Rizk S, Guillén-Boixet J, Franzmann TM, Jahnel M, Marrone L, Chang YT, Sterneckert J, Tomancak P, Hyman AA, Alberti S (2018) RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science 360:918–921. https://doi.org/10.1126/science.aar7366
Mansur F, Ivshina M, Gu W, Schaevitz L, Stackpole E, Gujja S, Edwards YJ, Richter JD (2016) Gld2-catalyzed 3′ monoadenylation of miRNAs in the hippocampus has no detectable effect on their stability or on animal behavior. RNA 22:1492–1499. https://doi.org/10.1261/rna.056937.116
Mateju D, Eichenberger B, Voigt F, Eglinger J, Roth G, Chao JA (2020) Single-molecule imaging reveals translation of mRNAs localized to stress granules. Cell 183:1801–1812. https://doi.org/10.1016/j.cell.2020.11.010
Mikl M, Vendra G, Kiebler MA (2011) Independent localization of MAP2, CaMKIIα and β-actin RNAs in low copy numbers. EMBO Rep 12:1077–1084. https://doi.org/10.1038/embor.2011.149
Miller S, Yasuda M, Coats JK, Jones Y, Martone ME, Mayford M (2002) Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36:507–519. https://doi.org/10.1016/s0896-6273(02)00978-9
Monahan Z, Ryan VH, Janke AM, Burke KA, Rhoads SN, Zerze GH, O'Meally R, Dignon GL, Conicella AE, Zheng W, Best RB, Cole RN, Mittal J, Shewmaker F, Fawzi NL (2017) Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J 36:2951–2967. https://doi.org/10.15252/embj.201696394
Mori Y, Imaizumi K, Katayama T, Yoneda T, Tohyama M (2000) Two cis-acting elements in the 3′ untranslated region of alpha-CaMKII regulate its dendritic targeting. Nat Neurosci 3:1079–1084. https://doi.org/10.1038/80591
Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, St KCF, George-Hyslop P (2015) ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88:678–690. https://doi.org/10.1016/j.neuron.2015.10.030
Na Y, Park S, Lee C, Kim DK, Park JM, Sockanathan S, Huganir RL, Worley PF (2016) Real-time imaging reveals properties of glutamate-induced arc/Arg 3.1 translation in neuronal dendrites. Neuron 91:561–573. https://doi.org/10.1016/j.neuron.2016.06.017
Nakayama K, Ohashi R, Shinoda Y, Yamazaki M, Abe M, Fujikawa A, Shigenobu S, Futatsugi A, Noda M, Mikoshiba K, Furuichi T, Sakimura K, Shiina N (2017) RNG105/caprin 1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation. elife 6:e29677. https://doi.org/10.7554/eLife.29677
Narayanan U, Nalavadi V, Nakamoto M, Pallas DC, Ceman S, Bassell GJ, Warren ST (2007) FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A. J Neurosci 27:14349–14357. https://doi.org/10.1523/JNEUROSCI.2969-07.2007
Nedelsky NB, Taylor JP (2022) Pathological phase transitions in ALS-FTD impair dynamic RNA-protein granules. RNA 28:97–113. https://doi.org/10.1261/rna.079001.121
Ohashi R, Shiina N (2020) Cataloguing and selection of mRNAs localized to dendrites in neurons and regulated by RNA-binding proteins in RNA granules. Biomol Ther 10:167. https://doi.org/10.3390/biom10020167
Padrón A, Ingolia N (2022) Analyzing the composition and organization of ribonucleoprotein complexes by APEX-Seq. Methods Mol Biol 2428:277–289. https://doi.org/10.1007/978-1-0716-1975-9_17
Park HY, Lim H, Yoon YJ, Follenzi A, Nwokafor C, Lopez-Jones M, Meng X, Singer RH (2014) Visualization of dynamics of single endogenous mRNA labeled in live mouse. Science 343:422–424. https://doi.org/10.1126/science.1239200
Ratti A, Buratti E (2016) Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem 138(Suppl 1):95–111. https://doi.org/10.1111/jnc.13625
Ries RJ, Zaccara S, Klein P, Olarerin-George A, Namkoong S, Pickering BF, Patil DP, Kwak H, Lee JH, Jaffrey SR (2019) m6A enhances the phase separation potential of mRNA. Nature 571:424–428. https://doi.org/10.1038/s41586-019-1374-1
Rook MS, Lu M, Kosik KS (2000) CaMKIIalpha 3′ untranslated region-directed mRNA translocation in living neurons: visualization by GFP linkage. J Neurosci 20:6385–6393. https://doi.org/10.1523/JNEUROSCI.20-17-06385.2000
Roy R, Shiina N, Wang DO (2020) More dynamic, more quantitative, unexpectedly intricate: advanced understanding on synaptic RNA localization in learning and memory. Neurobiol Learn Mem 168:107149. https://doi.org/10.1016/j.nlm.2019.107149
Ryan VH, Fawzi NL (2019) Physiological, pathological, and targetable membraneless organelles in neurons. Trends Neurosci 42:693–708. https://doi.org/10.1016/j.tins.2019.08.005
Shiina N (2019) Liquid- and solid-like RNA granules form through specific scaffold proteins and combine into biphasic granules. J Biol Chem 294:3532–3548. https://doi.org/10.1074/jbc.RA118.005423
Shiina N, Shinkura K, Tokunaga M (2005) A novel RNA-binding protein in neuronal RNA granules: regulatory machinery for local translation. J Neurosci 25:4420–4434. https://doi.org/10.1523/JNEUROSCI.0382-05.2005
Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP (2017) Spatiotemporal control of intracellular phase transitions using light-activated opto droplets. Cell 168:159–171.e14. https://doi.org/10.1016/j.cell.2016.11.054
Siemen H, Colas D, Heller HC, Brüstle O, Pera RA (2011) Pumilio-2 function in the mouse nervous system. PLoS One 6:e25932. https://doi.org/10.1371/journal.pone.0025932
Sudhakaran IP, Ramaswami M (2017) Long-term memory consolidation: the role of RNA-binding proteins with prion-like domains. RNA Biol 14:568–586. https://doi.org/10.1080/15476286.2016.1244588
Sutton MA, Schuman EM (2006) Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127:49–58. https://doi.org/10.1016/j.cell.2006.09.014
Tang SJ, Meulemans D, Vazquez L, Colaco N, Schuman E (2001) A role for a rat homolog of staufen in the transport of RNA to neuronal dendrites. Neuron 32:463–475. https://doi.org/10.1016/s0896-6273(01)00493-7
The Dutch-Belgian Fragile X Consortium, Bakker CE, Verheij C, Willemsen R, van der Helm R, Willems PJ (1994) Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 78:23–33. https://doi.org/10.1016/0092-8674(94)90569-X
Tsang B, Arsenault J, Vernon RM, Lin H, Sonenberg N, Wang LY, Bah A, Forman-Kay JD (2019) Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation. Proc Natl Acad Sci U S A 116:4218–4227. https://doi.org/10.1073/pnas.1814385116
Tushev G, Glock C, Heumüller M, Biever A, Jovanovic M, Schuman EM (2018) Alternative 3' UTRs modify the localization, regulatory potential, stability, and plasticity of mRNAs in neuronal compartments. Neuron 98:495–511.e6. https://doi.org/10.1016/j.neuron.2018.03.030
Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM, Anilkumar S, Ivshina M, Hurt JA, Nagaoka K, Nalavadi VC, Lorenz LJ, Bassell GJ, Akbarian S, Chattarji S, Klann E, Richter JD (2013) Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med 19:1473–1477. https://doi.org/10.1038/nm.3353
Uutela M, Lindholm J, Louhivuori V, Wei H, Louhivuori LM, Pertovaara A, Akerman K, Castrén E, Castrén ML (2012) Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. Genes Brain Behav 11:513–523. https://doi.org/10.1111/j.1601-183X.2012.00784.x
Vessey JP, Macchi P, Stein JM, Mikl M, Hawker KN, Vogelsang P, Wieczorek K, Vendra G, Riefler J, Tübing F, Aparicio SA, Abel T, Kiebler MA (2008) A loss of function allele for murine Staufen 1 leads to impairment of dendritic Staufen1-RNP delivery and dendritic spine morphogenesis. Proc Natl Acad Sci U S A 105:16374–16379. https://doi.org/10.1073/pnas.0804583105
Yoon YJ, Wu B, Buxbaum AR, Das S, Tsai A, English BP, Grimm JB, Lavis LD, Singer RH (2016) Glutamate-induced RNA localization and translation in neurons. Proc Natl Acad Sci U S A 113:E6877–E6886. https://doi.org/10.1073/pnas.1614267113
Zalcman G, Federman N, Romano A (2018) CaMKII isoforms in learning and memory: localization and function. Front Mol Neurosci 11:445. https://doi.org/10.3389/fnmol.2018.00445
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Shiina, N. (2023). Regulation of Neuronal RNA Granule Dynamics Through Phase Separation in Memory Formation and Disease. In: Kurokawa, R. (eds) Phase Separation in Living Cells. Springer, Singapore. https://doi.org/10.1007/978-981-99-4886-4_10
Download citation
DOI: https://doi.org/10.1007/978-981-99-4886-4_10
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-99-4885-7
Online ISBN: 978-981-99-4886-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)