Top

Published in:

Open Access 01-11-2016 | Original Paper

Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP

Authors: Pritha Majumder, Jen-Fei Chu, Biswanath Chatterjee, Krishna B. S. Swamy, Che-Kun James Shen

Published in: Acta Neuropathologica | Issue 5/2016

Abstract

For proper mammalian brain development and functioning, the translation of many neuronal mRNAs needs to be repressed without neuronal activity stimulations. We have discovered that the expression of a subclass of neuronal proteins essential for neurodevelopment and neuron plasticity is co-regulated at the translational level by TDP-43 and the Fragile X Syndrome protein FMRP. Using molecular, cellular and imaging approaches, we show that these two RNA-binding proteins (RBP) co-repress the translation initiation of Rac1, Map1b and GluR1 mRNAs, and consequently the hippocampal spinogenesis. The co-repression occurs through binding of TDP-43 to mRNA(s) at specific UG/GU sequences and recruitment of the inhibitory CYFIP1-FMRP complex by its glycine-rich domain. This novel regulatory scenario could be utilized to silence a significant portion of around 160 common target mRNAs of the two RBPs. The study establishes a functional/physical partnership between FMRP and TDP-43 that mechanistically links several neurodevelopmental disorders and neurodegenerative diseases.

Available only for authorised users

Aakalu G, Smith WB, Nguyen N, Jiang C, Schuman EM (2001) Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron 30:489–502CrossRefPubMed

Abbeduto L, McDuffie A, Thurman AJ (2014) The fragile X syndrome-autism comorbidity: what do we really know? Front Genet 5:355. doi:10.3389/fgene.2014.00355 CrossRefPubMedPubMedCentral

Abekhoukh S, Bardoni B (2014) CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome. Front Cell Neurosci 8:81. doi:10.3389/fncel.2014.00081 CrossRefPubMedPubMedCentral

Baralle M, Buratti E, Baralle FE (2013) The role of TDP-43 in the pathogenesis of ALS and FTLD. Biochem Soc Trans 41:1536–1540. doi:10.1042/BST20130186 CrossRefPubMed

Bechara EG, Didiot MC, Melko M, Davidovic L, Bensaid M, Martin P, Castets M, Pognonec P, Khandjian EW, Moine H et al (2009) A novel function for fragile X mental retardation protein in translational activation. PLoS Biol 7:e16. doi:10.1371/journal.pbio.1000016 CrossRefPubMed

Bongmba OY, Martinez LA, Elhardt ME, Butler K, Tejada-Simon MV (2011) Modulation of dendritic spines and synaptic function by Rac1: a possible link to Fragile X syndrome pathology. Brain Res 1399:79–95. doi:10.1016/j.brainres.2011.05.020 CrossRefPubMedPubMedCentral

Bose JK, Wang IF, Hung L, Tarn WY, Shen CK (2008) TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. J Biol Chem 283:28852–28859. doi:10.1074/jbc.M805376200 CrossRefPubMedPubMedCentral

Bray N (2016) Neurodegenerative disease: repeating mistakes. Nat Rev Neurosci. doi:10.1038/nrn.2016.64

Brown V, Jin P, Ceman S, Darnell JC, O’Donnell WT, Tenenbaum SA, Jin X, Feng Y, Wilkinson KD, Keene JD et al (2001) Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107:477–487CrossRefPubMed

10.

Buffington SA, Huang W, Costa-Mattioli M (2014) Translational control in synaptic plasticity and cognitive dysfunction. Annu Rev Neurosci 37:17–38. doi:10.1146/annurev-neuro-071013-014100 CrossRefPubMedPubMedCentral

11.

Ceman S, O’Donnell WT, Reed M, Patton S, Pohl J, Warren ST (2003) Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet 12:3295–3305. doi:10.1093/hmg/ddg350 CrossRefPubMed

12.

Chen E, Joseph S (2015) Fragile X mental retardation protein: a paradigm for translational control by RNA-binding proteins. Biochimie 114:147–154. doi:10.1016/j.biochi.2015.02.005 CrossRefPubMedPubMedCentral

13.

Corbetta S, Gualdoni S, Ciceri G, Monari M, Zuccaro E, Tybulewicz VL, de Curtis I (2009) Essential role of Rac1 and Rac3 GTPases in neuronal development. FASEB J 23:1347–1357. doi:10.1096/fj.08-121574 CrossRefPubMed

14.

Coyne AN, Siddegowda BB, Estes PS, Johannesmeyer J, Kovalik T, Daniel SG, Pearson A, Bowser R, Zarnescu DC (2014) Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. J Neurosci 34:15962–15974. doi:10.1523/JNEUROSCI.2526-14.2014 CrossRefPubMedPubMedCentral

15.

Coyne AN, Yamada SB, Siddegowda BB, Estes PS, Zaepfel BL, Johannesmeyer JS, Lockwood DB, Pham LT, Hart MP, Cassel JA et al (2015) Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Hum Mol Genet 24:6886–6898. doi:10.1093/hmg/ddv389 PubMed

16.

Darnell JC, Klann E (2013) The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci 16:1530–1536. doi:10.1038/nn.3379 CrossRefPubMedPubMedCentral

17.

Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW et al (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–261. doi:10.1016/j.cell.2011.06.013 CrossRefPubMedPubMedCentral

18.

De Rubeis S, Bagni C (2011) Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders. J Neurodev Disord 3:257–269. doi:10.1007/s11689-011-9087-2 CrossRefPubMedPubMedCentral

19.

Ebert DH, Greenberg ME (2013) Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493:327–337. doi:10.1038/nature11860 CrossRefPubMedPubMedCentral

20.

El Fatimy R, Tremblay S, Dury AY, Solomon S, De Koninck P, Schrader JW, Khandjian EW (2012) Fragile X mental retardation protein interacts with the RNA-binding protein caprin1 in neuronal RIBONUCLEOPROTEIN complexes [corrected]. PLoS One 7:e39338. doi:10.1371/journal.pone.0039338 CrossRefPubMedPubMedCentral

21.

Fernandez-Moya SM, Bauer KE, Kiebler MA (2014) Meet the players: local translation at the synapse. Front Mol Neurosci 7:84. doi:10.3389/fnmol.2014.00084 CrossRefPubMedPubMedCentral

22.

Fernandez E, Rajan N, Bagni C (2013) The FMRP regulon: from targets to disease convergence. Front Neurosci 7:191. doi:10.3389/fnins.2013.00191 CrossRefPubMedPubMedCentral

23.

Ferron L, Nieto-Rostro M, Cassidy JS, Dolphin AC (2014) Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density. Nat Commun 5:3628. doi:10.1038/ncomms4628 CrossRefPubMedPubMedCentral

24.

Freibaum BD, Chitta RK, High AA, Taylor JP (2010) Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9:1104–1120. doi:10.1021/pr901076y CrossRefPubMedPubMedCentral

25.

Gerstberger S, Hafner M, Tuschl T (2014) A census of human RNA-binding proteins. Nat Rev Genet 15:829–845. doi:10.1038/nrg3813 CrossRefPubMed

26.

Guo W, Polich ED, Su J, Gao Y, Christopher DM, Allan AM, Wang M, Wang F, Wang G, Zhao X (2015) Fragile X proteins FMRP and FXR2P control synaptic GluA1 expression and neuronal maturation via distinct mechanisms. Cell Rep 11:1651–1666. doi:10.1016/j.celrep.2015.05.013 CrossRefPubMedPubMedCentral

27.

Ishizuka A, Siomi MC, Siomi H (2002) A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes Dev 16:2497–2508. doi:10.1101/gad.1022002 CrossRefPubMedPubMedCentral

28.

Jayaseelan S, Tenenbaum SA (2012) Neurodevelopmental disorders: signalling pathways of fragile X syndrome. Nature 492:359–360. doi:10.1038/nature11764 CrossRefPubMed

29.

Jovicic A, Paul JW 3rd, Gitler AD (2016) Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia. J Neurochem. doi:10.1111/jnc.13642 PubMed

30.

Kapeli K, Yeo GW (2012) Genome-wide approaches to dissect the roles of RNA binding proteins in translational control: implications for neurological diseases. Front Neurosci 6:144. doi:10.3389/fnins.2012.00144 CrossRefPubMedPubMedCentral

31.

Kazdoba TM, Leach PT, Silverman JL, Crawley JN (2014) Modeling fragile X syndrome in the Fmr1 knockout mouse. Intractable Rare Dis Res 3:118–133. doi:10.5582/irdr.2014.01024 CrossRefPubMedPubMedCentral

32.

Kern JK, Geier DA, Sykes LK, Geier MR (2013) Evidence of neurodegeneration in autism spectrum disorder. Transl Neurodegener 2:17. doi:10.1186/2047-9158-2-17 CrossRefPubMedPubMedCentral

33.

Khandjian EW, Huot ME, Tremblay S, Davidovic L, Mazroui R, Bardoni B (2004) Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles. Proc Natl Acad Sci 101:13357–13362. doi:10.1073/pnas.0405398101 CrossRefPubMedPubMedCentral

34.

Krichevsky AM, Kosik KS (2001) Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32:683–696CrossRefPubMed

35.

Kroon T, Sierksma MC, Meredith RM (2013) Investigating mechanisms underlying neurodevelopmental phenotypes of autistic and intellectual disability disorders: a perspective. Front Syst Neurosci 7:75. doi:10.3389/fnsys.2013.00075 CrossRefPubMedPubMedCentral

36.

La Fata G, Gartner A, Dominguez-Iturza N, Dresselaers T, Dawitz J, Poorthuis RB, Averna M, Himmelreich U, Meredith RM, Achsel T et al (2014) FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry. Nat Neurosci 17:1693–1700. doi:10.1038/nn.3870 CrossRefPubMed

37.

Laggerbauer B, Ostareck D, Keidel EM, Ostareck-Lederer A, Fischer U (2001) Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum Mol Genet 10:329–338CrossRefPubMed

38.

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. doi:10.1093/hmg/ddq137 CrossRefPubMedPubMedCentral

39.

Lai MC, Lee YH, Tarn WY (2008) The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. Mol Biol Cell 19:3847–3858. doi:10.1091/mbc.E07-12-1264 CrossRefPubMedPubMedCentral

40.

Lee A, Li W, Xu K, Bogert BA, Su K, Gao FB (2003) Control of dendritic development by the Drosophila fragile X-related gene involves the small GTPase Rac1. Development 130:5543–5552. doi:10.1242/dev.00792 CrossRefPubMed

41.

Lee EB, Lee VM, Trojanowski JQ (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13:38–50. doi:10.1038/nrn3121

42.

Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. doi:10.1016/j.neuron.2013.07.033 CrossRefPubMedPubMedCentral

43.

Liu-Yesucevitz L, Bassell GJ, Gitler AD, Hart AC, Klann E, Richter JD, Warren ST, Wolozin B (2011) Local RNA translation at the synapse and in disease. J Neurosci 31:16086–16093. doi:10.1523/JNEUROSCI.4105-11.2011 CrossRefPubMedPubMedCentral

44.

Maiti P, Manna J, Ilavazhagan G, Rossignol J, Dunbar GL (2015) Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases. Neurosci Biobehav Rev 59:208–237. doi:10.1016/j.neubiorev.2015.09.020 CrossRefPubMed

45.

Majumder P, Chen YT, Bose JK, Wu CC, Cheng WC, Cheng SJ, Fang YH, Chen YL, Tsai KJ, Lien CC et al (2012) TDP-43 regulates the mammalian spinogenesis through translational repression of Rac1. Acta Neuropathol 124:231–245. doi:10.1007/s00401-012-1006-4 CrossRefPubMed

46.

Menon L, Mader SA, Mihailescu MR (2008) Fragile X mental retardation protein interactions with the microtubule associated protein 1B RNA. RNA 14:1644–1655. doi:10.1261/rna.1100708 CrossRefPubMedPubMedCentral

47.

Muddashetty RS, Kelic S, Gross C, Xu M, Bassell GJ (2007) Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J Neurosci 27:5338–5348. doi:10.1523/JNEUROSCI.0937-07.2007 CrossRefPubMed

48.

Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M et al (2008) The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134:1042–1054. doi:10.1016/j.cell.2008.07.031 CrossRefPubMed

49.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. doi:10.1126/science.1134108 CrossRefPubMed

50.

Osterweil EK, Krueger DD, Reinhold K, Bear MF (2010) Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J Neurosci 30:15616–15627. doi:10.1523/JNEUROSCI.3888-10.2010 CrossRefPubMedPubMedCentral

51.

Plante I, Davidovic L, Ouellet DL, Gobeil LA, Tremblay S, Khandjian EW, Provost P (2006) Dicer-derived microRNAs are utilized by the fragile X mental retardation protein for assembly on target RNAs. J Biomed Biotechnol 2006:1–12. doi:10.1155/JBB/2006/64347

52.

Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C et al (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14:459–468. doi:10.1038/nn.2779 CrossRefPubMedPubMedCentral

53.

Pozueta J, Lefort R, Ribe EM, Troy CM, Arancio O, Shelanski M (2013) Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nat Commun 4:1939. doi:10.1038/ncomms2927 CrossRefPubMedPubMedCentral

54.

Re A, Joshi T, Kulberkyte E, Morris Q, Workman CT (2014) RNA-protein interactions: an overview. Methods Mol Biol 1097:491–521. doi:10.1007/978-1-62703-709-9_23 CrossRefPubMed

55.

Santoro MR, Bray SM, Warren ST (2012) Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol 7:219–245. doi:10.1146/annurev-pathol-011811-132457 CrossRefPubMed

56.

Sekiyama N, Arthanari H, Papadopoulos E, Rodriguez-Mias RA, Wagner G, Leger-Abraham M (2015) Molecular mechanism of the dual activity of 4EGI-1: dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1. Proc Natl Acad Sci 112:E4036–E4045. doi:10.1073/pnas.1512118112 CrossRefPubMedPubMedCentral

57.

Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J et al (2011) Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J Biol Chem 286:1204–1215. doi:10.1074/jbc.M110.190884 CrossRefPubMed

58.

Sephton CF, Yu G (2015) The function of RNA-binding proteins at the synapse: implications for neurodegeneration. Cell Mol Life Sci 72:3621–3635. doi:10.1007/s00018-015-1943-x CrossRefPubMedPubMedCentral

59.

Sidorov MS, Auerbach BD, Bear MF (2013) Fragile X mental retardation protein and synaptic plasticity. Mol Brain 6:15. doi:10.1186/1756-6606-6-15 CrossRefPubMedPubMedCentral

60.

Stefani G, Fraser CE, Darnell JC, Darnell RB (2004) Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci 24:7272–7276. doi:10.1523/JNEUROSCI.2306-04.2004 CrossRefPubMed

61.

Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, Konig J, Hortobagyi T, Nishimura AL, Zupunski V et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458. doi:10.1038/nn.2778 CrossRefPubMedPubMedCentral

62.

Triller A, Sheng M (2012) Synaptic structure and function. Curr Opin Neurobiol 22:363–365. doi:10.1016/j.conb.2012.04.002 CrossRefPubMed

63.

Vanden Broeck L, Callaerts P, Dermaut B (2014) TDP-43-mediated neurodegeneration: towards a loss-of-function hypothesis? Trends Mol Med 20:66–71. doi:10.1016/j.molmed.2013.11.003 CrossRefPubMed

64.

Vasilyev N, Polonskaia A, Darnell JC, Darnell RB, Patel DJ, Serganov A (2015) Crystal structure reveals specific recognition of a G-quadruplex RNA by a beta-turn in the RGG motif of FMRP. Proc Natl Acad Sci 112:E5391–E5400. doi:10.1073/pnas.1515737112 CrossRefPubMedPubMedCentral

65.

Wang H (2015) Fragile X mental retardation protein: from autism to neurodegenerative disease. Front Cell Neurosci 9:43. doi:10.3389/fncel.2015.00043 PubMedPubMedCentral

66.

Wang IF, Wu LS, Chang HY, Shen CK (2008) TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J Neurochem 105:797–806. doi:10.1111/j.1471-4159.2007.05190.x CrossRefPubMed

67.

Wang IF, Wu LS, Shen CK (2008) TDP-43: an emerging new player in neurodegenerative diseases. Trends Mol Med 14:479–485. doi:10.1016/j.molmed.2008.09.001 CrossRefPubMed

68.

Wu LS, Cheng WC, Hou SC, Yan YT, Jiang ST, Shen CK (2010) TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48:56–62. doi:10.1002/dvg.20584 PubMed

69.

Wu LS, Cheng WC, Shen CK (2012) Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem 287:27335–27344. doi:10.1074/jbc.M112.359000 CrossRefPubMedPubMedCentral

70.

Yu Z, Fan D, Gui B, Shi L, Xuan C, Shan L, Wang Q, Shang Y, Wang Y (2012) Neurodegeneration-associated TDP-43 interacts with fragile X mental retardation protein (FMRP)/Staufen (STAU1) and regulates SIRT1 expression in neuronal cells. J Biol Chem 287:22560–22572. doi:10.1074/jbc.M112.357582 CrossRefPubMedPubMedCentral

71.

Zalfa F, Achsel T, Bagni C (2006) mRNPs, polysomes or granules: FMRP in neuronal protein synthesis. Curr Opin Neurobiol 16:265–269. doi:10.1016/j.conb.2006.05.010 CrossRefPubMed

72.

Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C (2003) The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112:317–327CrossRefPubMed

Title: Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP
Authors: Pritha Majumder
Jen-Fei Chu
Biswanath Chatterjee
Krishna B. S. Swamy
Che-Kun James Shen
Publication date: 01-11-2016
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1603-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2016

TREM1 facilitates microglial phagocytosis of amyloid beta

Down-regulation of neuronal L1 cell adhesion molecule expression alleviates inflammatory neuronal injury

Activating NRF1-BRAF and ATG7-RAF1 fusions in anaplastic pleomorphic xanthoastrocytoma without BRAF p.V600E mutation

Extended post-mortem delay times should not be viewed as a deterrent to the scientific investigation of human brain tissue: a study from the Brains for Dementia Research Network Neuropathology Study Group, UK

Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease

Frequent alternative lengthening of telomeres and ATRX loss in adult NF1-associated diffuse and high-grade astrocytomas