Document Detail


Protection of mouse retinal ganglion cell axons and soma from glaucomatous and ischemic injury by cytoplasmic overexpression of Nmnat1.
MedLine Citation:
PMID:  23211826     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The Wlds mutation affords protection of retinal ganglion cell (RGC) axons in retinal ischemia and in inducible and hereditary preclinical models of glaucoma. We undertook the present study to determine whether the Nmnat1 portion of the chimeric protein provides axonal and somatic protection of RGCs in models of ischemia and glaucoma, particularly when localized to nonnuclear regions of the cell.
METHODS: The survival and integrity of RGC axons and soma from transgenic mice with confirmed cytoplasmic overexpression of Nmnat1 in retina and optic nerve (cytNmnat1-Tg mice) were examined in the retina and postlaminar optic nerve 4 days following acute retinal ischemia, and 3 weeks following the chronic elevation of intraocular pressure.
RESULTS: Ischemia- and glaucoma-induced disruptions of proximal segments of RGC axons that comprise the nerve fiber layer in wild-type mice were both robustly abrogated in cytNmnat1-Tg mice. More distal portions of RGC axons within the optic nerve were also protected from glaucomatous disruption in the transgenic mice. In both disease models, Nmnat1 overexpression in extranuclear locations significantly enhanced the survival of RGC soma.
CONCLUSIONS: Overexpression of Nmnat1 in the cytoplasm and axons of RGCs robustly protected against both ischemic and glaucomatous loss of RGC axonal integrity, as well as loss of RGC soma. These findings reflect the more pan-cellular protection of CNS neurons that is realized by cytoplasmic Nmnat1 expression, and thus provide a therapeutic strategy for protecting against retinal neurodegeneration, and perhaps other CNS neurodegenerative diseases as well.
Authors:
Yanli Zhu; Lihong Zhang; Yo Sasaki; Jeffrey Milbrandt; Jeffrey M Gidday
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-02
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  54     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-02-21     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  25-36     Citation Subset:  IM    
Affiliation:
Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Axons / enzymology,  pathology*
Cell Survival
Cytoplasm / enzymology
Cytoprotection
Disease Models, Animal
Fluorescent Antibody Technique, Indirect
Gene Expression Regulation, Enzymologic / physiology*
Glaucoma / enzymology,  prevention & control*
Immunoblotting
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Microscopy, Confocal
Nicotinamide-Nucleotide Adenylyltransferase / genetics*
Optic Nerve / enzymology
Optic Neuropathy, Ischemic / enzymology,  pathology,  prevention & control*
Retina / enzymology
Retinal Diseases / enzymology,  pathology,  prevention & control*
Retinal Ganglion Cells / enzymology,  pathology*
Grant Support
ID/Acronym/Agency:
AG13730/AG/NIA NIH HHS; EY02687/EY/NEI NIH HHS; EY18607/EY/NEI NIH HHS; P30 NS057105/NS/NINDS NIH HHS; R01 AG013730/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
EC 2.7.7.1/Nicotinamide-Nucleotide Adenylyltransferase; EC 2.7.7.1/Nmnat1 protein, mouse
Comments/Corrections

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