Dataset Information

A Ca²⁺-Dependent Switch Activates Axonal Casein Kinase 2α Translation and Drives G3BP1 Granule Disassembly for Axon Regeneration.

ABSTRACT: The main limitation on axon regeneration in the peripheral nervous system (PNS) is the slow rate of regrowth. We recently reported that nerve regeneration can be accelerated by axonal G3BP1 granule disassembly, releasing axonal mRNAs for local translation to support axon growth. Here, we show that G3BP1 phosphorylation by casein kinase 2α (CK2α) triggers G3BP1 granule disassembly in injured axons. CK2α activity is temporally and spatially regulated by local translation of Csnk2a1 mRNA in axons after injury, but this requires local translation of mTor mRNA and buffering of the elevated axonal Ca²⁺ that occurs after axotomy. CK2α's appearance in axons after PNS nerve injury correlates with disassembly of axonal G3BP1 granules as well as increased phospho-G3BP1 and axon growth, although depletion of Csnk2a1 mRNA from PNS axons decreases regeneration and increases G3BP1 granules. Phosphomimetic G3BP1 shows remarkably decreased RNA binding in dorsal root ganglion (DRG) neurons compared with wild-type and non-phosphorylatable G3BP1; combined with other studies, this suggests that CK2α-dependent G3BP1 phosphorylation on Ser 149 after axotomy releases axonal mRNAs for translation. Translation of axonal mRNAs encoding some injury-associated proteins is known to be increased with Ca²⁺ elevations, and using a dual fluorescence recovery after photobleaching (FRAP) reporter assay for axonal translation, we see that translational specificity switches from injury-associated protein mRNA translation to CK2α translation with endoplasmic reticulum (ER) Ca²⁺ release versus cytoplasmic Ca²⁺ chelation. Our results point to axoplasmic Ca²⁺ concentrations as a determinant for the temporal specificity of sequential translational activation of different axonal mRNAs as severed axons transition from injury to regenerative growth.

SUBMITTER: Sahoo PK

PROVIDER: S-EPMC8182743 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Polyglutamine diseases are a group of neurodegenerative disorders caused by an abnormal expansion of CAG repeat tracts in the codifying regions of nine, otherwise unrelated, genes. While the protein products of these genes are suggested to play diverse cellular roles, the pathogenic mutant proteins bearing an expanded polyglutamine sequence share a tendency to self-assemble, aggregate and engage in abnormal molecular interactions. Understanding the shared paths that link polyglutamine protein expansion to the nervous system dysfunction and the degeneration that takes place in these disorders is instrumental to the identification of targets for therapeutic intervention. Among polyglutamine diseases, spinocerebellar ataxias (SCAs) share many common aspects, including the fact that they involve dysfunction of the cerebellum, resulting in ataxia. Our work aimed at exploring a putative new therapeutic target for the two forms of SCA with higher worldwide prevalence, SCA type 2 (SCA2) and type 3 (SCA3), which are caused by expanded forms of ataxin-2 (ATXN2) and ataxin-3 (ATXN3), respectively. The pathophysiology of polyglutamine diseases has been described to involve an inability to properly respond to cell stress. We evaluated the ability of GTPase-activating protein-binding protein 1 (G3BP1), an RNA-binding protein involved in RNA metabolism regulation and stress responses, to counteract SCA2 and SCA3 pathology, using both in vitro and in vivo disease models. Our results indicate that G3BP1 overexpression in cell models leads to a reduction of ATXN2 and ATXN3 aggregation, associated with a decrease in protein expression. This protective effect of G3BP1 against polyglutamine protein aggregation was reinforced by the fact that silencing G3bp1 in the mouse brain increases human expanded ATXN2 and ATXN3 aggregation. Moreover, a decrease of G3BP1 levels was detected in cells derived from patients with SCA2 and SCA3, suggesting that G3BP1 function is compromised in the context of these diseases. In lentiviral mouse models of SCA2 and SCA3, G3BP1 overexpression not only decreased protein aggregation but also contributed to the preservation of neuronal cells. Finally, in an SCA3 transgenic mouse model with a severe ataxic phenotype, G3BP1 lentiviral delivery to the cerebellum led to amelioration of several motor behavioural deficits. Overall, our results indicate that a decrease in G3BP1 levels may be a contributing factor to SCA2 and SCA3 pathophysiology, and that administration of this protein through viral vector-mediated delivery may constitute a putative approach to therapy for these diseases, and possibly other polyglutamine disorders.

Dataset Information

A Ca²⁺-Dependent Switch Activates Axonal Casein Kinase 2α Translation and Drives G3BP1 Granule Disassembly for Axon Regeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

A Ca2+-Dependent Switch Activates Axonal Casein Kinase 2α Translation and Drives G3BP1 Granule Disassembly for Axon Regeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A Ca²⁺-Dependent Switch Activates Axonal Casein Kinase 2α Translation and Drives G3BP1 Granule Disassembly for Axon Regeneration.