Dephosphorylation-Induced Ubiquitination and Degradation of FMRP in Dendrites: A Role in Immediate Early mGluR-Stimulated Translation

Nalavadi, Vijayalaxmi; Muddashetty, Ravi; Groß, Christina; Bassell, Gary J.

doi:10.1523/jneurosci.5057-11.2012

Cited by 114 publications

(133 citation statements)

References 33 publications

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“…6,7 FMRP normally represses the translation of its mRNA targets, the release of this repression being coupled with its dephosphorylation in response to an activation signal, which results in a burst of local protein synthesis. 8,9 In fragile X syndrome neurons, however, a subset of dendritic proteins synthesis is constitutively elevated due to the lack of FMRP even in the absence of an activation signal. 10 FMRP has been shown to use its RGG box domain to bind mRNA targets that form G-quadruplex structures.…”

Section: Introductionmentioning

confidence: 99%

FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

et al. 2014

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Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, is caused by the loss of expression of the fragile X mental retardation protein (FMRP). FMRP, which regulates the transport and translation of specific mRNAs, uses its RGG box domain to bind mRNA targets that form G-quadruplex structures. One of the FMRP in vivo targets, Shank1 mRNA, encodes the master scaffold proteins of the postsynaptic density (PSD) which regulate the size and shape of dendritic spines because of their capacity to interact with many different PSD components. Due to their effect on spine morphology, altered translational regulation of Shank1 transcripts may contribute to the FXS pathology. We hypothesized that the FMRP interactions with Shank1 mRNA are mediated by the recognition of the G quadruplex structure, which has not been previously demonstrated. In this study we used biophysical techniques to analyze the Shank1 mRNA 3'-UTR and its interactions with FMRP and its phosphorylated mimic FMRP S500D. We found that the Shank1 mRNA 3 0 -UTR adopts two very stable intramolecular G-quadruplexes which are bound specifically and with high affinity by FMRP both in vitro and in vivo. These results suggest a role of G-quadruplex RNA motif as a structural element in the common mechanism of FMRP regulation of its dendritic mRNA targets.

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Section: Introductionmentioning

confidence: 99%

FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

et al. 2014

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“…A similar regulation of phosphorylation, occurring only in mature neurons and depending on effectors downstream of NMDARs, has already been described for CREB, a transcription factor that is widely implicated in synaptic plasticity and memory formation (21). Dephosphorylation and subsequent proteasomal degradation is also commonly used for a prompt regulation of protein functions: among others, the levels of the fragile X syndrome-associated protein FMRP are controlled at the synapses through a dephosphorylation-dependent proteasome-mediated degradation (23).…”

Section: Discussionmentioning

confidence: 70%

Synaptic Synthesis, Dephosphorylation, and Degradation

Montanara

Rusconi

Locarno

et al. 2015

Journal of Biological Chemistry

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Background: Although associated with intellectual disability, CDKL5 functions and regulation are poorly understood. Results: Upon neuronal activation, CDKL5 is dynamically regulated through local synthesis, dephosphorylation, and degradation. Conclusion: Neuronal activity and maturation control CDKL5 phosphorylation state and expression. Significance: This is the first report showing the activity-dependent modulation of CDKL5 in the neuronal periphery, further linking it to synapse development and plasticity.

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“…In addition, as Tomo-1 and HRD1 colocalize to dendrites where they likely interact, the potential exists for localized regulation of Tomo-1 protein level within, or near, postsynaptic sites. A rapid, potentially local, degradation of Tomo-1 may occur in a similar fashion to dephosphorylationinduced, UPS-mediated degradation of fragile X mental retardation protein (FMRP) in the dendrites and synapses of cultured rat neurons (71). Specific E3 ubiquitin ligases are known to influence synaptic physiology and plasticity in both non-proteolytic (72) and proteolyticdependent manners (73).…”

Section: Discussionmentioning

confidence: 99%

The ubiquitin-proteasome system functionally links neuronal Tomosyn-1 to dendritic morphology

Saldate¹,

Shiau

Cazares

et al. 2018

Journal of Biological Chemistry

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Altering the expression of Tomosyn-1 (Tomo-1), a soluble, R-SNARE domaincontaining protein, significantly affects behavior in mice, Drosophila, and Caenorhabditis elegans. Yet, the mechanisms that modulate Tomo-1 expression and its regulatory activity remain poorly defined. Here, we found that Tomo-1 expression levels influence postsynaptic spine density. Tomo-1 overexpression increased dendritic spine density, while Tomo-1 knockdown (KD) decreased spine density. These findings identified a novel action of Tomo-1 on dendritic spines, which is unique because it occurs independently of Tomo-1's C-terminal R-SNARE domain. We also demonstrate that the ubiquitinproteasome system (UPS), which is known to influence synaptic strength, dynamically regulates Tomo-1 protein levels. Immunoprecipitated and affinity-purified Tomo-1 from cultured rat hippocampal neurons was ubiquitinated, and the levels of ubiquitinated Tomo-1 dramatically increased upon pharmacological proteasome blockade. Moreover, Tomo-1 ubiquitination appeared to be mediated through an interaction with the E3 ubiquitin ligase HRD1, as immunoprecipitation of Tomo-1 from neurons coprecipitated HRD1, and this interaction increases upon proteasome inhibition. Further, in vitro reactions indicated direct, HRD1 concentrationdependent Tomo-1 ubiquitination. We also noted that the UPS regulates both Tomo-1 expression and functional output, as HRD1 KD in hippocampal neurons increased Tomo-1 protein level and dendritic spine density. Notably, the effect of HRD1 KD on spine density was mitigated by additional KD of Tomo-1, indicating a direct HRD1/Tomo-1 effector relationship. In summary, our results indicate that the UPS is likely to participate in tuning synaptic efficacy and spine dynamics by precise regulation of neuronal Tomo-1 levels.

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Dephosphorylation-Induced Ubiquitination and Degradation of FMRP in Dendrites: A Role in Immediate Early mGluR-Stimulated Translation

Cited by 114 publications

References 33 publications

FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

Synaptic Synthesis, Dephosphorylation, and Degradation

The ubiquitin-proteasome system functionally links neuronal Tomosyn-1 to dendritic morphology

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