Role of Rho Kinase Pathway in Chondroitin Sulfate Proteoglycan-Mediated Inhibition of Neurite Outgrowth in PC12 Cells
Abstract
Activation of the Rho kinase (ROCK) pathway has been associated with inhibition of neurite regeneration and outgrowth in spinal cord injury. Growth-inhibitory substances present in the glial scar such as chondroitin sulfate proteoglycans (CSPGs) have been shown to create a nonpermissive environment for axon regeneration that results in growth cone collapse. In this study, an in vitro model was developed in nerve growth factor-differentiated PC12 cells where the Rho/ROCK pathway was modulated by CSPG. CSPG elicited concentration-dependent inhibition of neurite outgrowth in PC12 cells, which was reversed by ROCK inhibitors such as fasudil, dimethylfasudil, and Y27632. Further studies on the interactions of CSPG with ROCK inhibitors revealed that the modulation of ROCK by CSPG is noncompetitive in nature. It was also observed that ROCK inhibitors increased neurite outgrowth in undifferentiated PC12 cells, indicating constitutive ROCK activity in the cells. Analysis of signaling pathways demonstrated that the effect of CSPG increases the phosphorylation of myosin phosphatase, a substrate immediately downstream of ROCK activation. Fasudil, dimethylfasudil, and Y27632 inhibited the phosphorylation of myosin phosphatase induced by CSPG with rank order potencies comparable to those observed in the neurite outgrowth assay. In addition, ROCK inhibitors reversed cofilin phosphorylation induced by CSPG with similar rank order potencies. Taken together, our data demonstrate that the inter…
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RhoA integrates molecular signals to organize sophisticated and coordinated variations in gene expression and actin cytoskeleton, crucial processes for neurite outgrowth and synaptic connectivity.
“It integrates molecular signals to organize sophisticated and coordinated variations in gene expression and actin cytoskeleton, crucial processes for the neurite outgrowth and synaptic connectivity [53,54].”
From Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome (2022) · cites this paper as [54]
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Progress towards biocompatible intracortical microelectrodes for neural interfacing applications
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Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons
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Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome
Parente, M., Tonini, C., Buzzelli, V., Carbone, E., Trezza, V., & Pallottini, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063408 · Cited by 11 · see citing works
“It integrates molecular signals to organize sophisticated and coordinated variations in gene expression and actin cytoskeleton, crucial processes for the neurite outgrowth and synaptic connectivity [53,54].”
Background
- Authors
- Gopalakrishnan, S. M., Teusch, N., Imhof, C., Bakker, M. H. M., Schurdak, M., Burns, D. J., & Warrior, U.
- Affiliations
- Abbott (United States) (US)
- Abbott (Germany) (DE)
- Corresponding author
- Gopalakrishnan, Sujatha M.
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2008-04-25
- Volume
- 86
- Issue
- 10
- Pages
- 2214-2226
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2003586842
- Cited by
- 62
- References
- 1
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 4
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- Rho kinase, chondroitin sulfate proteoglycans, neurite outgrowth, PC12 cells, fasudil, Y-27632, myosin phosphatase, cofilin phosphorylation, ROCK inhibitor, axon regeneration, glial scar, spinal cord injury, nerve growth factor differentiation
- MeSH terms
- Animals, Enzyme Inhibitors, Phosphorylation, Chondroitin Sulfate Proteoglycans, Signal Transduction, Neurites, PC12 Cells, Myosin-Light-Chain Phosphatase, Cofilin 1, Rats, rho-Associated Kinases
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