Axoplasmic Importins Enable Retrograde Injury Signaling in Lesioned Nerve

Hanz, Shlomit; Perlson, Eran; Willis, Dianna E.; Zheng, Joanna J.; Massarwa, Rada; Huerta, J.J.; Koltzenburg, M; Köhler, M; van-Minnen, Jan; Twiss, Jeffery L.; Fainzilber, Mike

doi:10.1016/s0896-6273(03)00770-0

Cited by 443 publications

(439 citation statements)

References 38 publications

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“…During the development of the nervous system, guided axon growth requires intra-axonal mRNA translation, and it is thus not surprising that local protein synthesis is also crucial for axon regeneration. The formation of a new growth cone after axotomy of developing axons in vitro requires both local protein synthesis and degradation [30], and upon injury of mature axons, mRNAs and protein synthesis machinery are rapidly recruited into axons and intraaxonal translation is upregulated or re-activated within these mature axons [31][32][33][34]. Locally synthesized proteins are required for communication from the injured axons to their soma and likely participate in the formation of the growth bulb at the site of injury [35,36].…”

Section: Regeneration After Nerve Injurymentioning

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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Section: Regeneration After Nerve Injurymentioning

confidence: 99%

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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“…In fact, many of them are important for repair or regeneration [26][27][28] . Here, we demonstrated that the key factors in WD included NGF, MAG, CNTF, CTNNA2, p53, JAK2, PLCB1, STAT3, BDNF, PRKC, collagen II, FGF, THBS4, TNC and c-Src (Fig.…”

Section: Kegg Analysis Of Genes Differentially Expressed During Wd Bamentioning

confidence: 99%

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

Yao

Shen

et al. 2013

Neurosci. Bull.

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Wallerian degeneration (WD) remains an important research topic. Many genes are differentially expressed during the process of WD, but the precise mechanisms responsible for these differentiations are not completely understood. In this study, we used microarrays to analyze the expression changes of the distal nerve stump at 0, 1, 4, 7, 14, 21 and 28 days after sciatic nerve injury in rats. The data revealed 6 076 differentially-expressed genes, with 23 types of expression, specifically enriched in genes associated with nerve development and axonogenesis, cytokine biosynthesis, cell differentiation, cytokine/chemokine production, neuron differentiation, cytokinesis, phosphorylation and axon regeneration. Kyoto Encyclopedia of Genes and Genomes pathway analysis gave findings related mainly to the MAPK signaling pathway, the Jak-STAT signaling pathway, the cell cycle, cytokine-cytokine receptor interaction, the p53 signaling pathway and the Wnt signaling pathway. Some key factors were NGF, MAG, CNTF, CTNNA2, p53, JAK2, PLCB1, STAT3, BDNF, PRKC, collagen II, FGF, THBS4, TNC and c-Src, which were further validated by real-time quantitative PCR, Western blot, and immunohistochemistry. Our findings contribute to a better understanding of the functional analysis of differentially-expressed genes in WD and may shed light on the molecular mechanisms of nerve degeneration and regeneration.

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“…Lysates were cleared by centrifugation at 16,000 ϫ g for 15 min, 4°C. Axoplasm was prepared as described by squeezing unfixed segments of nerve in ice-cold NTB (33). Protein content was normalized by Bradford assay (Bio-Rad).…”

Section: Isolation Of Axonsmentioning

confidence: 99%

Sumoylation in axons triggers retrograde transport of the RNA-binding protein La

Niekerk

Willis

Chang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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A surprisingly large population of mRNAs has been shown to localize to sensory axons, but few RNA-binding proteins have been detected in these axons. These axonal mRNAs include several potential binding targets for the La RNA chaperone protein. La is transported into axonal processes in both culture and peripheral nerve. Interestingly, La is posttranslationally modified in sensory neurons by sumoylation. In axons, small ubiquitin-like modifying polypeptides (SUMO)-La interacts with dynein, whereas native La interacts with kinesin. Lysine 41 is required for sumoylation, and sumoylation-incompetent La K41R shows only anterograde transport, whereas WT La shows both anterograde and retrograde transport in axons. Thus, sumoylation of La determines the directionality of its transport within the axonal compartment, with SUMO-La likely recycling to the cell body.axonal transport ͉ La/SSB ͉ RNA localization ͉ small ubiquitin-like modifying polypeptide

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Axoplasmic Importins Enable Retrograde Injury Signaling in Lesioned Nerve

Cited by 443 publications

References 38 publications

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

Sumoylation in axons triggers retrograde transport of the RNA-binding protein La

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