RNAi pathway is functional in peripheral nerve axons

Murashov, Alexander K.; Chintalgattu, Vishnu; Islamov, R. R.; Lever, Teresa E.; Pak, Elena S.; Sierpinski, Paulina; Katwa, Laxmansa C.; Scott, Michael R. Van

doi:10.1096/fj.06-6155com

Cited by 86 publications

(74 citation statements)

References 69 publications

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“…We have previously demonstrated that FMRP is transported to the peripheral axons of rat nociceptors (Price et al, 2006). It is also known that FMRP localizes to axonal growth cones, where it is involved in regulating axonal growth (Antar et al, 2006), and that FMRP is associated with RNAi machinery in sensory axons (Murashov et al, 2007). Here, we have shown that intraplantar rapamycin inhibited second-phase formalin responses in wild-type but not KO mice, demonstrating a role for peripheral mTOR-mediated translation in this model.…”

Section: Discussionmentioning

confidence: 59%

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Price¹,

Rashid²,

Millecamps³

et al. 2007

J. Neurosci.

183

245

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Fragile X mental retardation is caused by silencing of the gene (FMR1) that encodes the RNA-binding protein (FMRP) that influences translation in neurons. A prominent feature of the human disorder is self-injurious behavior, suggesting an abnormality in pain processing. Moreover, FMRP regulates group I metabotropic glutamate receptor (mGluR1/5)-dependent plasticity, which is known to contribute to nociceptive sensitization. We demonstrate here, using the Fmr1 knock-out (KO) mouse, that FMRP plays an important role in pain processing because Fmr1 KO mice showed (1) decreased (ϳ50%) responses to ongoing nociception (phase 2, formalin test), (2) a 3 week delay in the development of peripheral nerve injury-induced allodynia, and (3) a near absence of wind-up responses in ascending sensory fibers after repetitive C-fiber stimulation. We provide evidence that the behavioral deficits are related to a mGluR1/5-and mammalian target of rapamycin (mTOR)-mediated mechanism because (1) spinal mGluR5 antagonism failed to inhibit the second phase of the formalin test, and we observed a marked reduction in nociceptive response to an intrathecal injection of an mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice; (2) peripheral DHPG injection had no effect in KO mice yet evoked thermal hyperalgesia in wild types; and (3) the mTOR inhibitor rapamycin inhibited formalin-and DHPG-induced nociception in wild-type but not Fmr1 KO mice. These experiments show that translation regulation via FMRP and mTOR is an important feature of nociceptive plasticity. These observations also support the hypothesis that the persistence of self-injurious behavior observed in fragile X mental retardation patients could be related to deficits in nociceptive sensitization.

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Section: Discussionmentioning

confidence: 59%

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Price¹,

Rashid²,

Millecamps³

et al. 2007

J. Neurosci.

183

245

View full text Add to dashboard Cite

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“…6). However, it has also been well documented that RNAi machinery exists in the peripheral nerve axons (57,58). Therefore, siRNA-mediated degradation of NaV1.8 mRNA could also occur in peripheral axons.…”

Section: Discussionmentioning

confidence: 99%

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

Ruangsri

Lin²,

Mulpuri

et al. 2011

Journal of Biological Chemistry

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“…This method to utilize axonal protein synthesis is complemented by the possibility of using RNA interference (RNAi) in axons to deplete selectively axons of specific mRNAs without changing the mRNA's abundance in other parts of the neurons. The RNAi is present and functional in developing axons of cultured dorsal root ganglion and superior cervical neurons [91,92], and in sciatic nerves [93]. More recently, we have found that injection of small interfering RNA (siRNA) into in the brain of adult mice can be used to deplete axons of mRNA [45].…”

Section: Toolsmentioning

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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RNAi pathway is functional in peripheral nerve axons

Cited by 86 publications

References 69 publications

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

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