Functional Axonal Regeneration Through Astrocytic Scar Genetically Modified to Digest Chondroitin Sulfate Proteoglycans

Overview

Journal J Neurosci

Specialty Neurology

Date 2007 Mar 3

PMID 17329414

Citations 107

Authors

William B J Cafferty

Shih-Hung Yang

Philip J Duffy

Shuxin Li

Stephen M Strittmatter

Affiliations

Soon will be listed here.

Abstract

Axotomized neurons within the damaged CNS are thought to be prevented from functional regeneration by inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors. Here, we provide a transgenic test of the role of CSPGs in limiting regeneration, using the gfap promotor to express a CSPG-degrading enzyme chondroitinase ABC (ChABC) in astrocytes. Corticospinal axons extend within the lesion site, but not caudal to it, after dorsal hemisection in the transgenic mice. The presence of the gfap-ChABC transgene yields no significant improvement in motor function recovery in this model. In contrast, functionally significant sensory axon regeneration is observed after dorsal rhizotomy in transgenic mice. These transgenic studies confirm a local efficacy for reduced CSPG to enhance CNS axon growth after traumatic injury. CSPGs appear to function in a spatially distinct role from myelin inhibitors, implying that combination-based therapy will be especially advantageous for CNS injuries.

Citing Articles

Astrocytic heterogeneous nuclear ribonucleoprotein U is involved in scar formation after spinal cord injury.

Quan L, Uyeda A, Manabe I, Muramatsu R J Neuroinflammation. 2025; 22(1):28.

PMID: 39891176 PMC: 11786496. DOI: 10.1186/s12974-025-03351-4.

A Modern Approach to the Treatment of Traumatic Brain Injury.

Syzdykbayev M, Kazymov M, Aubakirov M, Kurmangazina A, Kairkhanov E, Kazangapov R Medicines (Basel). 2024; 11(5).

PMID: 38786549 PMC: 11123131. DOI: 10.3390/medicines11050010.

Combined RhoA morpholino and ChABC treatment protects identified lamprey neurons from retrograde apoptosis after spinal cord injury.

Hu J, Zhang G, Rodemer W, Jin L, Selzer M Front Cell Neurosci. 2024; 17:1292012.

PMID: 38179205 PMC: 10764559. DOI: 10.3389/fncel.2023.1292012.

Brain Trauma and the Secondary Cascade in Humans: Review of the Potential Role of Vitamins in Reparative Processes and Functional Outcome.

Denniss R, Barker L Behav Sci (Basel). 2023; 13(5).

PMID: 37232626 PMC: 10215746. DOI: 10.3390/bs13050388.

Neuronal regeneration after injury: a new perspective on gene therapy.

Zeng C, Zhang C Front Neurosci. 2023; 17:1181816.

PMID: 37152598 PMC: 10160438. DOI: 10.3389/fnins.2023.1181816.

References

Ramer M, Priestley J, McMahon S . Functional regeneration of sensory axons into the adult spinal cord. Nature. 2000; 403(6767):312-6. DOI: 10.1038/35002084. View

Fournier A, Gould G, Liu B, Strittmatter S . Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin. J Neurosci. 2002; 22(20):8876-83. PMC: 6757674. View

Asher R, Morgenstern D, Fidler P, Adcock K, Oohira A, Braistead J . Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J Neurosci. 2000; 20(7):2427-38. PMC: 6772249. View

Yick L, Wu W, So K, Yip H, Shum D . Chondroitinase ABC promotes axonal regeneration of Clarke's neurons after spinal cord injury. Neuroreport. 2000; 11(5):1063-7. DOI: 10.1097/00001756-200004070-00032. View

Brosamle C, Huber A, Fiedler M, Skerra A, Schwab M . Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment. J Neurosci. 2000; 20(21):8061-8. PMC: 6772740. View

Romero M, Rangappa N, Garry M, Smith G . Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. J Neurosci. 2001; 21(21):8408-16. PMC: 6762793. View

Bonilla I, Tanabe K, Strittmatter S . Small proline-rich repeat protein 1A is expressed by axotomized neurons and promotes axonal outgrowth. J Neurosci. 2002; 22(4):1303-15. PMC: 6757578. View

Kim J, Li S, GrandPre T, Qiu D, Strittmatter S . Axon regeneration in young adult mice lacking Nogo-A/B. Neuron. 2003; 38(2):187-99. DOI: 10.1016/s0896-6273(03)00147-8. View

Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B . Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron. 2003; 38(2):201-11. DOI: 10.1016/s0896-6273(03)00226-5. View

10.

Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne M . Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron. 2003; 38(2):213-24. DOI: 10.1016/s0896-6273(03)00225-3. View

11.

Li S, Strittmatter S . Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J Neurosci. 2003; 23(10):4219-27. PMC: 6741116. View

12.

Darian-Smith C . Primary afferent terminal sprouting after a cervical dorsal rootlet section in the macaque monkey. J Comp Neurol. 2004; 470(2):134-50. DOI: 10.1002/cne.11030. View

13.

Bareyre F, Kerschensteiner M, Raineteau O, Mettenleiter T, Weinmann O, Schwab M . The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci. 2004; 7(3):269-77. DOI: 10.1038/nn1195. View

14.

Li W, Walus L, Rabacchi S, Jirik A, Chang E, Schauer J . A neutralizing anti-Nogo66 receptor monoclonal antibody reverses inhibition of neurite outgrowth by central nervous system myelin. J Biol Chem. 2004; 279(42):43780-8. DOI: 10.1074/jbc.M401803200. View

15.

Kim J, Liu B, Park J, Strittmatter S . Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron. 2004; 44(3):439-51. DOI: 10.1016/j.neuron.2004.10.015. View

16.

Berry M, Maxwell W, Logan A, Mathewson A, McConnell P, Ashhurst D . Deposition of scar tissue in the central nervous system. Acta Neurochir Suppl (Wien). 1983; 32:31-53. DOI: 10.1007/978-3-7091-4147-2_3. View

17.

Abad F, Feria M, Boada J . Chronic amitriptyline decreases autotomy following dorsal rhizotomy in rats. Neurosci Lett. 1989; 99(1-2):187-90. DOI: 10.1016/0304-3940(89)90287-5. View

18.

Schnell L, Schwab M . Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature. 1990; 343(6255):269-72. DOI: 10.1038/343269a0. View

19.

Levine J . Increased expression of the NG2 chondroitin-sulfate proteoglycan after brain injury. J Neurosci. 1994; 14(8):4716-30. PMC: 6577168. View

20.

Johnson W, Ruppe M, Rockenstein E, Price J, Sarthy V, Verderber L . Indicator expression directed by regulatory sequences of the glial fibrillary acidic protein (GFAP) gene: in vivo comparison of distinct GFAP-lacZ transgenes. Glia. 1995; 13(3):174-84. DOI: 10.1002/glia.440130304. View