Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice

Masato Koike; Masahiro Shibata; Yoshiyuki Ohsawa; Hiroshi Nakanishi; Tomoyuki Koga; Satoshi Kametaka; Satoshi Waguri; Takashi Momoi; Eiki Kominami; Christoph Peters; Kurt von Figura; Paul Saftig; Yasuo Uchiyama

doi:10.1016/s1044-7431(03)00035-6

Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice

Mol Cell Neurosci. 2003 Feb;22(2):146-61. doi: 10.1016/s1044-7431(03)00035-6.

Authors

Masato Koike¹, Masahiro Shibata, Yoshiyuki Ohsawa, Hiroshi Nakanishi, Tomoyuki Koga, Satoshi Kametaka, Satoshi Waguri, Takashi Momoi, Eiki Kominami, Christoph Peters, Kurt von Figura, Paul Saftig, Yasuo Uchiyama

Affiliation

¹ Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, 565-0871, Suita, Osaka, Japan.

PMID: 12676526
DOI: 10.1016/s1044-7431(03)00035-6

Abstract

To understand the mechanisms of retinal atrophy in cathepsin D-deficient mice, the postnatal development of their retinae was analyzed. TUNEL-positive cells appeared abundantly in the outer nuclear layer (ONL) and slightly in the inner nuclear layer (INL). Nitric oxide synthase (NOS) was induced in microglial cells which invaded retinal layers and phagocytosed dead cell debris, while NOS inhibitors prevented cell death in the INL but not in the ONL. Caspases 9 and 3 were activated only in the ONL after P15. Moreover, no atrophic change was detected in the retina of mice deficient in cathepsin B or L. These results suggest that cathepsin D is essential for the metabolic maintenance of retinal photoreceptor cells and that its deficiency induces apoptosis of the cells, while the loss of INL neurons is mediated by NO from microglial cells.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics*
Atrophy / genetics
Atrophy / metabolism*
Atrophy / physiopathology
Caspases / metabolism
Cathepsin D / deficiency*
Cathepsin D / genetics
DNA Damage / drug effects
DNA Damage / genetics
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Fluorescent Antibody Technique
Mice
Mice, Knockout
Microglia / metabolism
Microglia / ultrastructure
Microscopy, Electron
Nerve Degeneration / genetics
Nerve Degeneration / metabolism*
Nerve Degeneration / physiopathology
Neuronal Ceroid-Lipofuscinoses / genetics
Neuronal Ceroid-Lipofuscinoses / metabolism*
Neuronal Ceroid-Lipofuscinoses / physiopathology
Nitric Oxide / metabolism
Nitric Oxide Synthase / antagonists & inhibitors
Nitric Oxide Synthase / metabolism
Phagocytosis / drug effects
Phagocytosis / genetics
Photoreceptor Cells / metabolism
Photoreceptor Cells / pathology
Photoreceptor Cells / ultrastructure
Retina / growth & development
Retina / metabolism*
Retina / pathology
Retinal Diseases / genetics
Retinal Diseases / metabolism*
Retinal Diseases / physiopathology
Retinal Ganglion Cells / pathology
Retinal Ganglion Cells / ultrastructure

Substances

Enzyme Inhibitors
Nitric Oxide
Nitric Oxide Synthase
Caspases
Cathepsin D