Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth

Li, Hai; Kuwajima, Takaaki; Oakley, Derek H.; Nikulina, Elena; Hou, Jingli; Yang, Wan Seok; Lowry, Emily; Lamas, Nuno Jorge; Amoroso, Mackenzie W.; Croft, Gist F.; Hosur, Raghavendra; Wichterle, Hynek; Sebti, Saı̈d M.; Filbin, Marie T.; Stockwell, Brent R.; Henderson, Christopher E.

doi:10.1016/j.celrep.2016.06.013

Cited by 51 publications

(83 citation statements)

References 60 publications

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“…This growth promotion also requires an intact CaaX motif for post-translational prenylation of the axonally synthesized Cdc42 protein. On first glance, our growth data seem to contradict a study that used prenylation inhibitors to link the post-translational modification to slowed axon growth on myelinassociated glycoprotein (MAG), a substrate that inhibits axon growth (Li et al, 2016). In cultured neurons, highly selective FT inhibitors were more effective than GGT inhibitors for increasing axon growth (Li et al, 2016), but the combination of the two synergistically block prenylation (Roberts et al, 2008).…”

Section: Discussioncontrasting

confidence: 63%

Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth

Lee

Kar

Kawaguchi

et al. 2018

Preprint

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The small Rho-family GTPase CDC42 has long been known to have a role in cell motility and axon growth. The eukaryotic Cdc42 gene is alternatively spliced yielding mRNAs with two different 3'UTRs and distinct C-termini, which have CaaX and CCaX motifs for post-translational prenylation or palmitoylation, respectively. Palmitoylated CDC42 protein has been shown to contribute to dendrite maturation, while the prenylated CDC42 protein contributes to axon specification. Here, we show that the mRNA encoding prenylated CDC42 protein preferentially localizes into axons of cultured sensory neurons. We show that prenylated CDC42 promotes axon growth in cultured sensory neurons, but palmitoylated CDC42 does not affect axon growth. The growth promotion by prenylated CDC42 requires axonal localization of its mRNA and an intact C-terminal CaaX motif for post-translational modification of the encoded protein by prenylation. Prenylated CDC42 protein localizes to the periphery of growth cones, but this subcellular localization requires axonal targeting of its mRNA.Together, these data show that alternative splicing of the Cdc42 gene product generates an axon growth-promoting, locally synthesized prenylated CDC42 protein.

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Section: Discussioncontrasting

confidence: 63%

Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth

Lee

Kar

Kawaguchi

et al. 2018

Preprint

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“…Numerous screens have identified the transcription factors and RAGs that compose the axon regeneration program and its output of cytoskeletal remodelers, axon growth molecules, and guidance proteins (13,(46)(47)(48)(49)(50)(51)(52). These efforts have defined critical components of the axon regeneration process and have led to promising translational results, including growth onto inhibitory substrates and CNS axon regeneration in vivo (46,52). Here, we contribute to these efforts by probing for injury-activated proteins that induce the proregenerative program in primary mammalian neurons.…”

Section: An In Vitro Preconditioning Assay To Screen For Proregeneratmentioning

confidence: 99%

HSP90 is a chaperone for DLK and is required for axon injury signaling

Karney-Grobe

Russo

Frey

et al. 2018

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

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Peripheral nerve injury induces a robust proregenerative program that drives axon regeneration. While many regeneration-associated genes are known, the mechanisms by which injury activates them are less well-understood. To identify such mechanisms, we performed a loss-of-function pharmacological screen in cultured adult mouse sensory neurons for proteins required to activate this program. Well-characterized inhibitors were present as injury signaling was induced but were removed before axon outgrowth to identify molecules that block induction of the program. Of 480 compounds, 35 prevented injury-induced neurite regrowth. The top hits were inhibitors to heat shock protein 90 (HSP90), a chaperone with no known role in axon injury. HSP90 inhibition blocks injury-induced activation of the proregenerative transcription factor cJun and several regeneration-associated genes. These phenotypes mimic loss of the proregenerative kinase, dual leucine zipper kinase (DLK), a critical neuronal stress sensor that drives axon degeneration, axon regeneration, and cell death. HSP90 is an atypical chaperone that promotes the stability of signaling molecules. HSP90 and DLK show two hallmarks of HSP90–client relationships: (i) HSP90 binds DLK, and (ii) HSP90 inhibition leads to rapid degradation of existing DLK protein. Moreover, HSP90 is required for DLK stability in vivo, where HSP90 inhibitor reduces DLK protein in the sciatic nerve. This phenomenon is evolutionarily conserved in Drosophila. Genetic knockdown of Drosophila HSP90, Hsp83, decreases levels of Drosophila DLK, Wallenda, and blocks Wallenda-dependent synaptic terminal overgrowth and injury signaling. Our findings support the hypothesis that HSP90 chaperones DLK and is required for DLK functions, including proregenerative axon injury signaling.

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“…Intriguingly, the mechanism underlying statin‐induced neurite outgrowth involves the downstream enzymes geranylgeranyl transferase and farnesyl transferase, which are responsible for protein prenylation. Like statins, small molecule inhibitors of these enzymes enhance neurite outgrowth and axon regeneration (Li et al, ). Inhibition of prenylation likely has a multitude of effects on proteins that are posttranslationally modified and regulated by prenylation.…”

Section: Multi‐action Approachesmentioning

confidence: 99%

Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development

Kaplan

Bueno

Hua

et al. 2017

Developmental Dynamics

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The failure of damaged axons to regrow underlies disability in central nervous system injury and disease. Therapies that stimulate axon repair will be critical to restore function. Extensive axon regeneration can be induced by manipulation of oncogenes and tumor suppressors; however, it has been difficult to translate this into functional recovery in models of spinal cord injury. The current challenge is to maximize the functional integration of regenerating axons to recover motor and sensory behaviors. Insights into axonal growth and wiring during nervous system development are helping guide new approaches to boost regeneration and functional connectivity after injury in the mature nervous system. Here we discuss our current understanding of axonal behavior after injury and prospects for the development of drugs to optimize axon regeneration and functional recovery after CNS injury.

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Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth

Cited by 51 publications

References 60 publications

Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth

Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth

HSP90 is a chaperone for DLK and is required for axon injury signaling

Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development

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