Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-β-synthase mutant mouse

Preethi S. Ganapathy, Brent Moister, Penny Roon, Barbara A Mysona, Jennifer Duplantier, Ying Dun, Tracy K.V.E. Moister, Marlena J. Farley, Puttur D Prasad, Kebin Liu, Sylvia B Smith

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

PURPOSE. To determine the effects of endogenous elevation of homocysteine on the retina using the cystathionine -βsynthase (cbs) mutant mouse. METHODS. Retinal homocysteine in cbs mutant mice was measured by high-performance liquid chromatography (HPLC). Retinal cryosections from cbs-/- mice and cbs+/- mice were examined for histologic changes by light and electron microscopy. Morphometric analysis was performed on retinas of cbs+/- mice maintained on a high-methionine diet (cbs+/- HM). Changes in retinal gene expression were screened by microarray. RESULTS. HPLC analysis revealed an approximate twofold elevation in retinal homocysteine in cbs+/- mice and an approximate sevenfold elevation in cbs-/- mice. Distinct alterations in the ganglion, inner plexiform, inner nuclear, and epithelial layers were observed in retinas of cbs-/- and 1-year-old cbs-/- mice. Retinas of cbs-/- HM mice demonstrated an approximate 20% decrease in cells of the ganglion cell layer (GCL), which occurred as early as 5-weeks after onset of the HM diet. Microarray analysis revealed alterations in expression of several genes, including increased expression of Aven, Egr1, and Bat3 in retinas of cbs+/- HM mice. CONCLUSIONS. This study provides the first analysis of morphologic and molecular effects of endogenous elevations of retinal homocysteine in an in vivo model. Increased retinal homocysteine alters inner and outer retinal layers in cbs homozygous mice and older cbs heterozygous mice, and it primarily affects the cells of the GCL in younger heterozygous mice. Elevated retinal homocysteine alters expression of genes involved in endoplasmic reticular stress, N-methyl-D-aspartate (NMDA) receptor activation, cell cycle, and apoptosis.

Original languageEnglish (US)
Pages (from-to)4460-4470
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number9
DOIs
StatePublished - Dec 1 2009

Fingerprint

Cystathionine
Retinal Neurons
Homocysteine
Retina
Ganglia
Gene Expression
High Pressure Liquid Chromatography
Diet
Microarray Analysis
N-Methyl-D-Aspartate Receptors
Methionine

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-β-synthase mutant mouse. / Ganapathy, Preethi S.; Moister, Brent; Roon, Penny; Mysona, Barbara A; Duplantier, Jennifer; Dun, Ying; Moister, Tracy K.V.E.; Farley, Marlena J.; Prasad, Puttur D; Liu, Kebin; Smith, Sylvia B.

In: Investigative Ophthalmology and Visual Science, Vol. 50, No. 9, 01.12.2009, p. 4460-4470.

Research output: Contribution to journalArticle

Ganapathy, Preethi S. ; Moister, Brent ; Roon, Penny ; Mysona, Barbara A ; Duplantier, Jennifer ; Dun, Ying ; Moister, Tracy K.V.E. ; Farley, Marlena J. ; Prasad, Puttur D ; Liu, Kebin ; Smith, Sylvia B. / Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-β-synthase mutant mouse. In: Investigative Ophthalmology and Visual Science. 2009 ; Vol. 50, No. 9. pp. 4460-4470.
@article{56828d728d9c4d73a70fdd88263cb888,
title = "Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-β-synthase mutant mouse",
abstract = "PURPOSE. To determine the effects of endogenous elevation of homocysteine on the retina using the cystathionine -βsynthase (cbs) mutant mouse. METHODS. Retinal homocysteine in cbs mutant mice was measured by high-performance liquid chromatography (HPLC). Retinal cryosections from cbs-/- mice and cbs+/- mice were examined for histologic changes by light and electron microscopy. Morphometric analysis was performed on retinas of cbs+/- mice maintained on a high-methionine diet (cbs+/- HM). Changes in retinal gene expression were screened by microarray. RESULTS. HPLC analysis revealed an approximate twofold elevation in retinal homocysteine in cbs+/- mice and an approximate sevenfold elevation in cbs-/- mice. Distinct alterations in the ganglion, inner plexiform, inner nuclear, and epithelial layers were observed in retinas of cbs-/- and 1-year-old cbs-/- mice. Retinas of cbs-/- HM mice demonstrated an approximate 20{\%} decrease in cells of the ganglion cell layer (GCL), which occurred as early as 5-weeks after onset of the HM diet. Microarray analysis revealed alterations in expression of several genes, including increased expression of Aven, Egr1, and Bat3 in retinas of cbs+/- HM mice. CONCLUSIONS. This study provides the first analysis of morphologic and molecular effects of endogenous elevations of retinal homocysteine in an in vivo model. Increased retinal homocysteine alters inner and outer retinal layers in cbs homozygous mice and older cbs heterozygous mice, and it primarily affects the cells of the GCL in younger heterozygous mice. Elevated retinal homocysteine alters expression of genes involved in endoplasmic reticular stress, N-methyl-D-aspartate (NMDA) receptor activation, cell cycle, and apoptosis.",
author = "Ganapathy, {Preethi S.} and Brent Moister and Penny Roon and Mysona, {Barbara A} and Jennifer Duplantier and Ying Dun and Moister, {Tracy K.V.E.} and Farley, {Marlena J.} and Prasad, {Puttur D} and Kebin Liu and Smith, {Sylvia B}",
year = "2009",
month = "12",
day = "1",
doi = "10.1167/iovs.09-3402",
language = "English (US)",
volume = "50",
pages = "4460--4470",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "9",

}

TY - JOUR

T1 - Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-β-synthase mutant mouse

AU - Ganapathy, Preethi S.

AU - Moister, Brent

AU - Roon, Penny

AU - Mysona, Barbara A

AU - Duplantier, Jennifer

AU - Dun, Ying

AU - Moister, Tracy K.V.E.

AU - Farley, Marlena J.

AU - Prasad, Puttur D

AU - Liu, Kebin

AU - Smith, Sylvia B

PY - 2009/12/1

Y1 - 2009/12/1

N2 - PURPOSE. To determine the effects of endogenous elevation of homocysteine on the retina using the cystathionine -βsynthase (cbs) mutant mouse. METHODS. Retinal homocysteine in cbs mutant mice was measured by high-performance liquid chromatography (HPLC). Retinal cryosections from cbs-/- mice and cbs+/- mice were examined for histologic changes by light and electron microscopy. Morphometric analysis was performed on retinas of cbs+/- mice maintained on a high-methionine diet (cbs+/- HM). Changes in retinal gene expression were screened by microarray. RESULTS. HPLC analysis revealed an approximate twofold elevation in retinal homocysteine in cbs+/- mice and an approximate sevenfold elevation in cbs-/- mice. Distinct alterations in the ganglion, inner plexiform, inner nuclear, and epithelial layers were observed in retinas of cbs-/- and 1-year-old cbs-/- mice. Retinas of cbs-/- HM mice demonstrated an approximate 20% decrease in cells of the ganglion cell layer (GCL), which occurred as early as 5-weeks after onset of the HM diet. Microarray analysis revealed alterations in expression of several genes, including increased expression of Aven, Egr1, and Bat3 in retinas of cbs+/- HM mice. CONCLUSIONS. This study provides the first analysis of morphologic and molecular effects of endogenous elevations of retinal homocysteine in an in vivo model. Increased retinal homocysteine alters inner and outer retinal layers in cbs homozygous mice and older cbs heterozygous mice, and it primarily affects the cells of the GCL in younger heterozygous mice. Elevated retinal homocysteine alters expression of genes involved in endoplasmic reticular stress, N-methyl-D-aspartate (NMDA) receptor activation, cell cycle, and apoptosis.

AB - PURPOSE. To determine the effects of endogenous elevation of homocysteine on the retina using the cystathionine -βsynthase (cbs) mutant mouse. METHODS. Retinal homocysteine in cbs mutant mice was measured by high-performance liquid chromatography (HPLC). Retinal cryosections from cbs-/- mice and cbs+/- mice were examined for histologic changes by light and electron microscopy. Morphometric analysis was performed on retinas of cbs+/- mice maintained on a high-methionine diet (cbs+/- HM). Changes in retinal gene expression were screened by microarray. RESULTS. HPLC analysis revealed an approximate twofold elevation in retinal homocysteine in cbs+/- mice and an approximate sevenfold elevation in cbs-/- mice. Distinct alterations in the ganglion, inner plexiform, inner nuclear, and epithelial layers were observed in retinas of cbs-/- and 1-year-old cbs-/- mice. Retinas of cbs-/- HM mice demonstrated an approximate 20% decrease in cells of the ganglion cell layer (GCL), which occurred as early as 5-weeks after onset of the HM diet. Microarray analysis revealed alterations in expression of several genes, including increased expression of Aven, Egr1, and Bat3 in retinas of cbs+/- HM mice. CONCLUSIONS. This study provides the first analysis of morphologic and molecular effects of endogenous elevations of retinal homocysteine in an in vivo model. Increased retinal homocysteine alters inner and outer retinal layers in cbs homozygous mice and older cbs heterozygous mice, and it primarily affects the cells of the GCL in younger heterozygous mice. Elevated retinal homocysteine alters expression of genes involved in endoplasmic reticular stress, N-methyl-D-aspartate (NMDA) receptor activation, cell cycle, and apoptosis.

UR - http://www.scopus.com/inward/record.url?scp=70349244883&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349244883&partnerID=8YFLogxK

U2 - 10.1167/iovs.09-3402

DO - 10.1167/iovs.09-3402

M3 - Article

C2 - 19357353

AN - SCOPUS:70349244883

VL - 50

SP - 4460

EP - 4470

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 9

ER -