title: Protection of mouse retinal ganglion cell axons and soma from glaucomatous and ischemic injury by cytoplasmic overexpression of Nmnat1.
abstract: OBJECTIVE
  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.affiliation: Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhu
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gidday
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology / Q000473:pathology*; D002470:Cell Survival; D003593:Cytoplasm / Q000201:enzymology; D019610:Cytoprotection; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005901:Glaucoma / Q000201:enzymology / Q000517:prevention & control*; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics*; D009900:Optic Nerve / Q000201:enzymology; D018917:Optic Neuropathy, Ischemic / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D012160:Retina / Q000201:enzymology; D012164:Retinal Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000201:enzymology / Q000473:pathology*
chemical_list: D009612:Nicotinamide-Nucleotide Adenylyltransferase; C510972:Nmnat1 protein, mouse