Long-term expression of glial cell line-derived neurotrophic factor slows, but does not stop retinal degeneration in a model of retinitis pigmentosa

Masayuki Ohnaka, Katsuaki Miki, Yuan Yuan Gong, Rebecca Stevens, Takeshi Iwase, Sean F. Hackett, Peter A. Campochiaro

Research output: Contribution to journalArticlepeer-review

Abstract

Retinitis pigmentosa is a group of diseases in which one of hundreds of mutations causes death of rod photoreceptor cells and then cones gradually die from oxidative damage. As different mutations cause rod cell death by different mechanisms, mutation-specific treatments are needed. Another approach is to use a neurotrophic factor to promote photoreceptor survival regardless of the mechanism of cell death, and previous studies have demonstrated encouraging short-term results with gene transfer of glial cell line-derived neurotrophic factor (GDNF). We generated rd10 mice with doxycycline-inducible expression of GDNF in photoreceptors (Tet/IRBP/GDNF-rd10 mice) or retinal pigmented epithelial cells (Tet/VMD2/GDNF-rd10 mice). In doxycycline-treated Tet/IRBP/GDNF-rd10 mice, there was a 9.3 Ã - 10 4-fold increase in Gdnf mRNA at P35 and although it decreased over time, it was still increased by 9.4 Ã - 10 3-fold at P70. Gdnf mRNA was increased 4.5 Ã - 10 2-fold in doxycycline-treated Tet/VMD2/GDMF-rd10 mice at P35 and was not significantly decreased at P70. GDNF protein levels were increased about 2.3-fold at P35 and 30% at P70 in Tet/IRBP/GDNF-rd10 mice, and in Tet/VMD2/GDNF-rd10 mice they were increased 30% at P35 and not significantly increased at P70. Despite the difference in expression, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 mice had comparable significant increases in outer nuclear layer thickness and mean photopic and scotopic ERG b-wave amplitudes compared with rd10 mice at P35 which decreased, but was still significant at P70. Compared with rd10 mice, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 mice had comparable significant improvements in cone density at P50 that decreased, but were still significant at P70. These data indicate that despite a large difference in expression of GDNF, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 provide comparable slowing of photoreceptor degeneration, but cannot stop the degeneration.

Original languageEnglish (US)
Pages (from-to)1047-1053
Number of pages7
JournalJournal of Neurochemistry
Volume122
Issue number5
DOIs
StatePublished - Sep 2012

Keywords

  • apoptosis
  • cone photoreceptors
  • electroretinograms

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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