Silencing Nogo-A promotes functional recovery in demyelinating disease.

Abstract

OBJECTIVE:

To determine if suppressing Nogo-A, an axonal inhibitory protein, will promote functional recovery in a murine model of multiple sclerosis (MS).

METHODS:

A small interfering RNA was developed to specifically suppress Nogo-A (siRNA-NogoA). The siRNA-NogoA silencing effect was evaluated in vitro and in vivo via immunohistochemistry. The siRNA was administered intravenously in 2 models of experimental autoimmune encephalomyelitis (EAE). Axonal repair was measured by upregulation of GAP43. Enzyme-linked immunosorbent assay, flow cytometry, and (3)H-thymidine incorporation were used to determine immunological changes in myelin-specific T cells in mice with EAE.

RESULTS:

The siRNA-NogoA suppressed Nogo-A expression in vitro and in vivo. Systemic administration of siRNA-NogoA ameliorated EAE and promoted axonal repair, as demonstrated by enhanced GAP43+ axons in the lesions. Myelin-specific T-cell proliferation and cytokine production were unchanged in the siRNA-NogoA-treated mice.

INTERPRETATION:

Silencing Nogo-A in EAE promotes functional recovery. The therapeutic benefit appears to be mediated by axonal growth and repair, and is not attributable to changes in the encephalitogenic capacity of the myelin-specific T cells. Silencing Nogo-A may be a therapeutic option for MS patients to prevent permanent functional deficits caused by immune-mediated axonal damage.

• Authors: Yuhong Yang, Yue Liu, Ping Wei, Haiyan Peng, Ryan Winger, Rehana Z Hussain, Li-Hong Ben, Petra D Cravens, Anne R Gocke, Krishna Puttaparthi, Michael K Racke, Dana M McTigue, Amy E Lovett-Racke
• Journal: Annals of neurology (Ann Neurol) Vol. 67 Issue 4 Pg. 498-507 (Apr 2010) ISSN: 1531-8249 [Electronic] United States
• PMID: 20437585 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GAP-43 Protein
• Glycoproteins
• Myelin Basic Protein
• Myelin Proteins
• Myelin-Oligodendrocyte Glycoprotein
• Nogo Proteins
• Peptide Fragments
• RNA, Small Interfering
• Rtn4 protein, mouse
• myelin basic protein 1-11
• myelin oligodendrocyte glycoprotein (35-55)
• Interleukin-10
• 4-O-methyl-12-O-tetradecanoylphorbol 13-acetate
• Interferon-gamma
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, metabolism, pathology)
• Enzyme-Linked Immunosorbent Assay (methods)
• Flow Cytometry (methods)
• GAP-43 Protein (genetics, metabolism)
• Gene Expression Regulation (drug effects, genetics)
• Glycoproteins (adverse effects)
• Interferon-gamma (metabolism)
• Interleukin-10 (metabolism)
• Lymphocytes (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myelin Basic Protein (genetics, pharmacology)
• Myelin Proteins (genetics, metabolism)
• Myelin-Oligodendrocyte Glycoprotein
• Neuroblastoma
• Nogo Proteins
• Peptide Fragments (adverse effects, genetics, pharmacology)
• RNA, Small Interfering (genetics, therapeutic use)
• Spinal Cord (metabolism)
• Tetradecanoylphorbol Acetate (analogs & derivatives, pharmacology)
• Transfection (methods)