June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Age-dependent retinal abnormalities and neurodegeneration in the small kinky tail mutant
Author Affiliations & Notes
  • Erica L Macke
    Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Erika Henningsen
    Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Erik Jessen
    Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
    Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Hitoshi Higuchi
    Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Samuel Miller
    Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
    Biology, University of Indiana, Bloomington, Indiana, United States
  • Sakae Ikeda
    Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
    McPherson Eye Research Institute, Madison, Wisconsin, United States
  • Akihiro Ikeda
    Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States
    McPherson Eye Research Institute, Madison, Wisconsin, United States
  • Footnotes
    Commercial Relationships   Erica Macke, None; Erika Henningsen, None; Erik Jessen, None; Hitoshi Higuchi, None; Samuel Miller, None; Sakae Ikeda, None; Akihiro Ikeda, None
  • Footnotes
    Support  NIH R01 EY022086, a professorship from the Retina Research Foundation (Walter H. Helmerich Research Chair), P30 EY016665, NIH T32 GM007133
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4524. doi:
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    • Get Citation

      Erica L Macke, Erika Henningsen, Erik Jessen, Hitoshi Higuchi, Samuel Miller, Sakae Ikeda, Akihiro Ikeda; Age-dependent retinal abnormalities and neurodegeneration in the small kinky tail mutant. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4524.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The purpose of this study is to investigate the link between aging and age-dependent diseases at the molecular level. We study mouse mutants with accelerated aging to identify novel factors involved in these processes. The small kinky tail (skt) mutation leads to a kinked tail and small body size in mice. We have identified age-dependent retinal abnormalities and hippocampal neurodegeneration in skt mice. This study aims to further characterize the skt phenotypes and identify the causative gene.

Methods : Immunohistochemical analysis of retinal sections from 4, 8, and 16-week old skt mutants and heterozygous controls was performed to examine age-dependent phenotypes, including inflammation, stress response, and synaptic abnormalities. Retinal sections were stained with hematoxylin and eosin (H&E) to measure the outer nuclear layer thickness (ONLT). Brains of 2-year old mice were perfused with 4% PFA and used for H&E and immunohistochemical analysis. Genetic mapping of the skt mutation was performed using an F2 intercross (B6/LT-skt/skt x C3Sn.BLiA-Pde6b+/DnJ). The resulting 2.5Mbp region was sequenced on the Illumina HiSeq platform.

Results : We observe an increase in microglia in skt retina at 4 weeks, which persists past 8 weeks. Specifically, we observe a large increase in activated microglia in the ONL and retinal pigment epithelium (RPE) at 4 and 8 weeks of age. By 8 weeks of age, there is significant damage to the skt retina and a decrease in ONLT. Age-related abnormalities are also present in the synaptic layers of the retina at 8 weeks. The skt brain exhibits abnormalities in the hippocampal neurons, including an increase in a stress marker, glial fibrillary acidic protein (GFAP), a decrease in the axon number, and an increase in cell death. Additionally, skt mice exhibit a reduced lifespan compared to heterozygous controls. Via positional cloning, we have identified the causative mutation within chondroitin sulfate synthase 1 (Chsy1).

Conclusions : Our study has identified a novel function for Chsy1 in aging within the brain and retina. The causative mutation in Chsy1 induces a large increase in inflammatory cells that precedes retinal degeneration. These data suggest that inflammation could be the primary defect causing the neurodegeneration and reduced lifespan in skt mice.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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