Aberrant early-phase ERK inactivation impedes neuronal function in fragile X syndrome
Open accessAbstract
Fragile X syndrome (FXS) has so far resisted efforts to define the basic cellular defects caused by the absence of a single protein, fragile X mental retardation protein (FMRP), because the patients have a wide variety of symptoms of varying severity. Immature-appearing dendritic spines on neurons found in FXS patients and fmr1 -KO mice suggest a role for FMRP in modulating production of synaptic structural proteins. We isolated cortical synaptoneurosomes from WT and KO mice and studied MAPK pathway activation after group I metabotropic glutamate receptor (mGluR) stimulation. Here, we show that ERK in KO synaptoneurosomes is rapidly dephosphorylated upon mGluR1/5 stimulation, whereas it is phosphorylated in WT mice, suggesting that aberrant activation of phosphatases occurs in KO synapses in response to synaptic stimulation. In KO synapses, protein phosphatase 2A (PP2A) is overactivated after mGluR1 stimulation, and tyrosine phosphatase is overactivated after mGluR5 stimulation, causing the rapid deactivation of ERK. ERK activation can be restored in KO by pretreatment with phosphatase blockers; blocking of PP2A by okadaic acid could successfully restore normal ERK activation in KO synaptoneurosomes. We propose that overactivation of phosphatases in synapses may be a key deficit in FXS, which affects synaptic translation, transcription, and synaptic receptor regulation.
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Molecular signaling pathways that orchestrate protein synthesis, spine shape, and synaptic plasticity, such as mTOR and ERK, are impaired in fragile X syndrome, possibly because some FMRP target mRNAs encode members of second messenger cascades converging on ERK.
“The molecular signaling pathways orchestrating protein synthesis, spine shape, and synaptic plasticity, such as mTOR and ERK (Figure 2), are also impaired in FXS (72,(87)(88)(89), possibly because some FMRP target mRNAs encode members of second messenger cascades converging on ERK (88,89).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [88]
Fragile X leads to hyperactivity in the protein phosphatase PP2a, which inactivates MAPK, an enzyme with impaired activity in oligomer-exposed neurons.
“Fragile X also leads to hyperactivity in the protein phosphatase PP2a (Kim et al., 2008) which inactivates MAPK, an enzyme with impaired activity in oligomer-exposed neurons (Tong et al., 2001).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Kim et al., 2008
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The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580 · see citing works
Altered synaptic plasticity in a mouse model of fragile X mental retardation
Huber, K. M., Gallagher, S. M., Warren, S. T., & Bear, M. F. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122205699 · Cited by 1,349 · see citing works
Sequence and expression of a metabotropic glutamate receptor
Masu, M., Tanabe, Y., Tsuchida, K., Shigemoto, R., & Nakanishi, S. (1991) · Nature · doi:10.1038/349760a0 · Cited by 1,216 · see citing works
Brown, V., Jin, P., Ceman, S., Darnell, J. C., O'Donnell, W. T., Tenenbaum, S. A., Jin, X., Feng, Y., Wilkinson, K. D., Keene, J. D., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00568-2 · Cited by 1,109 · see citing works
Dendritic Protein Synthesis, Synaptic Plasticity, and Memory
Sutton, M. A., & Schuman, E. M. (2006) · Cell · doi:10.1016/j.cell.2006.09.014 · Cited by 894 · see citing works
Dendritic Spine Pathology: Cause or Consequence of Neurological Disorders?
Fiala, J. C., Spacek, J., & Harris, K. M. (2002) · Brain Research Reviews · doi:10.1016/s0165-0173(02)00158-3 · Cited by 811 · see citing works
Weiler, I. J., Irwin, S. A., Klintsova, A. Y., Spencer, C. M., Brazelton, A. D., Miyashiro, K., Comery, T. A., Patel, B., Eberwine, J., & Greenough, W. T. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5395 · Cited by 644 · cited 1× · see citing works
“In normal mice, FMRP is translated near synapses in response to group I mGluR activation (7, 28).”
BackgroundValjent, E., Pascoli, V., Svenningsson, P., Paul, S., Enslen, H., Corvol, J.-C., Stipanovich, A., Caboche, J., Lombroso, P. J., Nairn, A. C., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408305102 · Cited by 614 · see citing works
Evidence that fragile X mental retardation protein is a negative regulator of translation
Laggerbauer, B. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.4.329 · Cited by 571 · see citing works
Chalecka-Franaszek, E., & Chuang, D. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.15.8745 · Cited by 544 · see citing works
Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP
Yan, Q. J., Rammal, M., Tranfaglia, M., & Bauchwitz, R. P. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.06.004 · Cited by 521 · see citing works
RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice
Miyashiro, K. Y., Beckel-Mitchener, A., Purk, T. P., Becker, K. G., Barret, T., Liu, L., Carbonetto, S., Weiler, I. J., Greenough, W. T., & Eberwine, J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00034-5 · Cited by 495 · see citing works
Self-citationHou, L., Antion, M. D., Hu, D., Spencer, C. M., Paylor, R., & Klann, E. (2006) · Neuron · doi:10.1016/j.neuron.2006.07.005 · Cited by 469 · see citing works
The fragile X mental retardation protein inhibits translation via interacting with mRNA
Li, Z. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.11.2276 · Cited by 448 · see citing works
Metabotropic Glutamate Receptors 1 and 5 Differentially Regulate CA1 Pyramidal Cell Function
Mannaioni, G., Marino, M. J., Valenti, O., Traynelis, S. F., & Conn, P. J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-16-05925.2001 · Cited by 441 · see citing works
Biochemical mechanisms for translational regulation in synaptic plasticity
Klann, E., & Dever, T. E. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1557 · Cited by 422 · see citing works
Muddashetty, R. S., Kelić, S., Gross, C., Xu, M., & Bassell, G. J. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0937-07.2007 · Cited by 421 · see citing works
Alessi, D. R., Gomez, N., Moorhead, G., Lewis, T., Keyse, S. M., & Cohen, P. (1995) · Current Biology · doi:10.1016/s0960-9822(95)00059-5 · Cited by 365 · see citing works
Nosyreva, E. D., & Huber, K. M. (2006) · Journal of Neurophysiology · doi:10.1152/jn.01316.2005 · Cited by 292 · see citing works
Irwin, S. A., Idupulapati, M., Gilbert, M. E., Harris, J. B., Chakravarti, A. B., Rogers, E. J., Crisostomo, R. A., Larsen, B. P., Mehta, A., Alcantara, C. J., et al. (2002) · American Journal of Medical Genetics · doi:10.1002/ajmg.10500 · Cited by 270 · see citing works
Self-citationLi, J., Pelletier, M. R., Perez-Velazquez, J. L., & Carlen, P. L. (2002) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2001.1085 · Cited by 268 · see citing works
Metabotropic glutamate receptors trigger postsynaptic protein synthesis.
Weiler, I., & Greenough, W. (1993) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.90.15.7168 · Cited by 260 · see citing works
Self-citationGallagher, S. M., Daly, C. A., Bear, M. F., & Huber, K. M. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.5407-03.2004 · Cited by 254 · see citing works
Weiler, I. J., Spangler, C. C., Klintsova, A. Y., Grossman, A. W., Kim, S. H., Bertaina-Anglade, V., Khaliq, H., de Vries, F. E., Lambers, F. A. E., Hatia, F., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407533101 · Cited by 210 · see citing works
Self-citationCeman, S., Brown, V., & Warren, S. T. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.12.7925 · Cited by 181 · see citing works
Moult, P. R., Gladding, C. M., Sanderson, T. M., Fitzjohn, S. M., Bashir, Z. I., Molnar, E., & Collingridge, G. L. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4322-05.2006 · Cited by 172 · see citing works
FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts
Castets, M., Schaeffer, C., Bechara, E., Schenck, A., Khandjian, E. W., Luche, S., Moine, H., Rabilloud, T., Mandel, J.-L., & Bardoni, B. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi077 · Cited by 162 · see citing works
Volk, L. J., Daly, C. A., & Huber, K. M. (2006) · Journal of Neurophysiology · doi:10.1152/jn.00383.2005 · Cited by 150 · see citing works
Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons
Levinthal, D. J., & DeFranco, D. B. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410771200 · Cited by 126 · see citing works
Valenti, O., Conn, P. J., & Marino, M. J. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10081 · Cited by 125 · see citing works
Loss of the VHR dual-specific phosphatase causescell-cycle arrest and senescence
Rahmouni, S., Cerignoli, F., Alonso, A., Tsutji, T., Henkens, R., Zhu, C., Louis-Dit-Sully, C., Moutschen, M. P., Jiang, W. B., & Mustelin, T. (2006) · Nature Cell Biology · doi:10.1038/ncb1398 · Cited by 123 · see citing works
Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice
Wilson, B. M., & Cox, C. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610875104 · Cited by 121 · see citing works
Galvez, R., Gopal, A. R., & Greenough, W. T. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02363-1 · Cited by 118 · see citing works
Self-citationTyrosine phosphorylation of VHR phosphatase by ZAP-70
Alonso, A., Rahmouni, S., Williams, S., van Stipdonk, M. J. B., Jaroszewski, L., Godzik, A., Abraham, R. T., Schoenberger, S. P., & Mustelin, T. (2002) · Nature Immunology · doi:10.1038/ni856 · Cited by 103 · see citing works
Role of Protein Phosphatase 2A in mGluR5-regulated MEK/ERK Phosphorylation in Neurons
Mao, L., Yang, L., Arora, A. K., Choe, E. S., Zhang, G., Liu, Z., Fibuch, E. E., & Wang, J. Q. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411709200 · Cited by 93 · see citing works
Huang, C., & Hsu, K. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03527.x · Cited by 85 · see citing works
Hao, J., Michalek, C., Zhang, W., Zhu, M., Xu, X., & Mende, U. (2006) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2006.04.003 · Cited by 71 · see citing works
Garcia, L., Garcia, F., Llorens, F., Unzeta, M., Itarte, E., & Gómez, N. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02950-2 · Cited by 48 · see citing works
Takada, Y. K., Hashimoto, M., Kasahara, J., et al. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.070839 · Cited by 46 · see citing works
Permeability characteristics of erythrocyte membrane to okadaic acid and calyculin A
Namboodiripad, A. N., & Jennings, M. L. (1996) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1996.270.2.c449 · Cited by 43 · see citing works
Selectively enriched mRNAs in rat synaptoneurosomes
Sung, Y.-J., Weiler, I. J., Greenough, W. T., & Denman, R. B. (2004) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.03.013 · Cited by 27 · see citing works
Self-citationPhosphorylation of Ser166 in RGS5 by protein kinase C causes loss of RGS function
Moroi, K., Nishiyama, M., Kawabata, S.-I., et al. (2007) · Life Sciences · doi:10.1016/j.lfs.2007.04.022 · Cited by 14 · see citing works
The molecular basis of the Fragile X syndrome
Smail, H. O. (2023) · Journal of Experimental and Molecular Biology · doi:10.47743/jemb-2023-80 · Cited by 13 · see citing works
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- [19]Weiler IJ. In: The Molecular Basis of Fragile X Syndrome. Sung YJ, Denman RB, editors. Kerala, India: Research Signpost; 2005. pp. 201–215. [Google Scholar]
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- Authors
- Kim, S. H., Markham, J. A., Weiler, I. J., & Greenough, W. T.
- Affiliations
- *Beckman Institute,
- University of Illinois Urbana-Champaign (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-03-18
- Volume
- 105
- Issue
- 11
- Pages
- 4429-4434
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2393788
- OpenAlex
- W2167656355
- Cited by
- 97
- References
- 43
- Citations by year
- 2024: 3 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 10 · 2016: 4 · 2015: 6 · 2014: 2 · 2013: 5 · 2012: 9
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH-35321, R01MH035321, R37MH035321)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD07333, T32HD007333)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- fragile X syndrome, FMRP, MAPK signaling, group I metabotropic glutamate receptors, mGluR1, mGluR5, protein phosphatase 2A, protein tyrosine phosphatase, synaptoneurosomes, synaptic plasticity, dendritic spines, Fmr1 knockout mice, okadaic acid
- MeSH terms
- Animals, Enzyme Activation, Fragile X Syndrome, Neurons, Synapses, Time Factors, Protein Serine-Threonine Kinases, Receptors, Metabotropic Glutamate, Mice, Knockout, Mitogen-Activated Protein Kinase Kinases, Extracellular Signal-Regulated MAP Kinases, Mice, Fragile X Messenger Ribonucleoprotein 1
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