SMN regulates axonal local translation via miR-183/mTOR pathway

Kye, Min Jeong; Niederst, Emily; Wertz, Mary H.; Gonçalves, Inês do Carmo G.; Akten, Bikem; Dover, Katarzyna; Peters, Miriam; Rießland, Markus; Neveu, Pierre; Wirth, Brunhilde; Kosik, Kenneth S.; Sardi, S. Pablo; Monani, Umrao R.; Passini, Marco A.; Şahin, Mustafa

doi:10.1093/hmg/ddu350

Cited by 128 publications

(130 citation statements)

References 57 publications

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“…Notably, in stimulated SMN-knockdown cells, phospho-S6 immunostaining appeared diffuse throughout the cytoplasm, without peripheral accumulations. Apparently, our findings are in disagreement with the notion that SMN deficiency dysregulates mTOR activity (Kye et al, 2014). However, we do not exclude perturbed translational events downstream of mTOR.…”

Section: Smn Loss Of Function Depletes the Plasma Membrane Of Ribosomescontrasting

confidence: 99%

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SMN affects membrane remodelling and anchoring of the protein synthesis machinery

Gabanella

Pisani

Borreca

et al. 2016

Journal of Cell Science

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Disconnection between membrane signalling and actin networks can have catastrophic effects depending on cell size and polarity. The survival motor neuron (SMN) protein is ubiquitously involved in assembly of spliceosomal small nuclear ribonucleoprotein particles. Other SMN functions could, however, affect cellular activities driving asymmetrical cell surface expansions. Genes able to mitigate SMN deficiency operate within pathways in which SMN can act, such as mRNA translation, actin network and endocytosis. Here, we found that SMN accumulates at membrane protrusions during the dynamic rearrangement of the actin filaments. In addition to localization data, we show that SMN interacts with caveolin-1, which mediates anchoring of translation machinery components. Importantly, SMN deficiency depletes the plasma membrane of ribosomes, and this correlates with the failure of fibroblasts to extend membrane protrusions. These findings strongly support a relationship between SMN and membrane dynamics. We propose that SMN could assembly translational platforms associated with and governed by the plasma membrane. This activity could be crucial in cells that have an exacerbated interdependence of membrane remodelling and local protein synthesis.

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Section: Smn Loss Of Function Depletes the Plasma Membrane Of Ribosomescontrasting

confidence: 99%

“…It has been reported that dysregulated mTOR signalling occurs in the SMA disease context (Kye et al, 2014). This prompted us to verify whether, in our SMN-depleted cells, the perturbation of actin network combines with a reduced mTOR activity.…”

Section: Smn Loss Of Function Depletes the Plasma Membrane Of Ribosomesmentioning

confidence: 81%

SMN affects membrane remodelling and anchoring of the protein synthesis machinery

Gabanella

Pisani

Borreca

et al. 2016

Journal of Cell Science

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“…Similarly, reduced levels of survival of motor neuron (SMN) decrease axonal mRNA localization and human SMN1 mutations that alter the amount of functional protein are responsible for most SMA cases [42]. Reduced SMN levels, such as seen in SMA, cause increase expression of microRNA-138, which, in turn, leads to reduced local mammalian target of rapamycin synthesis and activity in axons [43]. For both these examples it has been suggested that impaired local translation of localized mRNAs at the neuromuscular junction contributes to the pathogenesis of ALS, SMA, and related disorders [44]; however, direct proof from in vivo studies is sparse.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.

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“…The mRNA expressions were calculated in accordance with a previous protocol [28]. Briefly, total RNA was reversely transcribed to cDNAs [Archiving Kit (Life Tech, USA)], which were then amplified [Power SyBr Green PCR Master Mix (Life Tech, USA)].…”

Section: Determination Of Expressions Of Mir-183 Mtor and Vegfmentioning

confidence: 99%

MicroRNA-183 Suppresses Neuropathic Pain and Expression of AMPA Receptors by Targeting mTOR/VEGF Signaling Pathway

Xie

et al. 2017

Cell Physiol Biochem

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Background: Neuropathic pain is a type of chronic pain that results from dysfunctions of the somatosensory nerve system. This study was aimed to investigate the effect of mTOR/VEGF signaling pathway on neuropathic pain and the regulation mechanisms of miR-183 on AMPA Receptors through mTOR/VEGF signaling pathway. Methods: Chronic compress injury (CCI) model was constructed in the current study, we used paw withdrawal mechanic threshold (PWMT) and paw withdrawal thermal latency (PWTL) to observe mTOR and VEGF receptors. Dual luciferase analysis, western blot and qRT-PCR were also applied to complete this experiment. Results: It was observed that the inhibition of mTOR and VEGF receptors could significantly relieve neuropathic pain in the CCI model. Moreover mTOR was confirmed as the direct target of miR-183. Furthermore, miR-183 could modulate VEGF through regulating mTOR expressions. We also found the expressions of AMPA receptors (i.e. GluR1 and GluR2), located in the downstream of mTOR/VEGF signaling pathway, were significantly upregulated when miR-183 was downregulated or when the mTOR/VEGF signaling pathway was activated. Conclusion: The inhibition of mTOR or VEGF receptors can significantly relieve neuropathic pain, and the upregulation of miR-183 can suppress AMPA receptors by inhibiting mTOR/VEGF pathway.

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SMN regulates axonal local translation via miR-183/mTOR pathway

Cited by 128 publications

References 57 publications

SMN affects membrane remodelling and anchoring of the protein synthesis machinery

SMN affects membrane remodelling and anchoring of the protein synthesis machinery

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

MicroRNA-183 Suppresses Neuropathic Pain and Expression of AMPA Receptors by Targeting mTOR/VEGF Signaling Pathway

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