Targeting chondroitinase ABC to axons enhances the ability of chondroitinase to promote neurite outgrowth and sprouting

Abstract

Background There is currently no effective treatment for promoting regeneration of injured nerves in patients who have sustained injury to the central nervous system such as spinal cord injury. Chondroitinase ABC is an enzyme, which promotes neurite outgrowth and regeneration. It has shown considerable promise as a therapy for these conditions. The aim of the study is to determine if targeting chondroitinase ABC expression to the neuronal axon can further enhance its ability to promote axon outgrowth. Long-distance axon regeneration has not yet been achieved, and would be a significant step in attaining functional recovery following spinal cord injury. Methodology/Principal findings To investigate this, neuronal cultures were transfected with constructs encoding axon-targeted chondroitinase, non-targeted chondroitinase or GFP, and the effects on neuron outgrowth and sprouting determined on substrates either permissive or inhibitory to neuron regeneration. The mechanisms underlying the observed effects were also explored. Targeting chondroitinase to the neuronal axon markedly enhances its ability to promote neurite outgrowth. The increase in neurite length is associated with an upregulation of β-integrin staining at the axonal cell surface. Staining for phosphofocal adhesion kinase, is also increased, indicating that the β-integrins are in an activated state. Expression of chondroitinase within the neurons also resulted in a decrease in expression of PTEN and RhoA, molecules which present a block to neurite outgrowth, thus identifying two of the pathways by which ChABC promotes neurite outgrowth. Conclusions / Significance The novel finding that targeting ChABC to the axon significantly enhances its ability to promote neurite extension, suggests that this may be an effective way of promoting long

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

“…Recent advances in the deployment of the chABC enzyme show promise. By targeting chABC to axons, neurite extension in SH-SY5Y neurons was significantly increased, even over cells that were transfected with a non-targeted variant of the enzyme ( Day et al, 2020 ). Despite the successes in animal models, no clinical trials using the enzyme have been reported.…”

Attenuation of the extracellular matrix restores microglial activity during the early stage of amyloidosis

“…RhoA/ROCK signaling has been implicated in Aβ‐induced responses of microglial cells (Zhang et al, 2019). As ChABC treatment may abrogate activation of RhoA‐ROCK pathway by chondroitin sulfates via PTPσ (Pendleton et al, 2013) and reduce expression of RhoA (Day, Alves, Daniell, Dasgupta, & Ogborne, 2020), we shall further investigate the relevance of this pathway in early microglia migration defects in AD mouse models and patients.…”

Aggrecan, the Primary Weight-Bearing Cartilage Proteoglycan, Has Context-Dependent, Cell-Directive Properties in Embryonic Development and Neurogenesis: Aggrecan Glycan Side Chain Modifications Convey Interactive Biodiversity

“…Removal of CS from the defect site by these enzymes resulted in recovery of neural functional properties [ 260 , 263 , 264 , 265 ]. Acute trauma to the brain and upper limbs resulting in neural damage have also been treated using chondroitinase ABC [ 266 , 267 ], resulting in neural sprouting through the defect site [ 268 ] and functional recovery [ 269 ].…”