Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration

Jen-Zen Chuang; Nan Yang; Nobuyuki Nakajima; Wataru Otsu; Cheng Fu; Howard Hua Yang; Maxwell Ping Lee; Armaan Fazal Akbar; Tudor Constantin Badea; Ziqi Guo; Afnan Nuruzzaman; Kuo-Shun Hsu; Joshua L Dunaief; Ching-Hwa Sung

doi:10.1038/s41467-021-27935-9

Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration

Nat Commun. 2022 Jan 18;13(1):374. doi: 10.1038/s41467-021-27935-9.

Authors

Jen-Zen Chuang^#¹, Nan Yang^#², Nobuyuki Nakajima^#^{2

3}, Wataru Otsu^#^{2

4}, Cheng Fu², Howard Hua Yang⁵, Maxwell Ping Lee⁵, Armaan Fazal Akbar⁶, Tudor Constantin Badea^{6

7}, Ziqi Guo², Afnan Nuruzzaman², Kuo-Shun Hsu^{2

8}, Joshua L Dunaief⁹, Ching-Hwa Sung^{10

11}

Affiliations

¹ Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. jzchuang@med.cornell.edu.
² Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
³ Department of Urology, Tokai University, Kanagawa, Japan.
⁴ Department of Biomedical Research Laboratory, Gifu Pharmaceutical University, Gifu, Japan.
⁵ The Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ National Eye Institute, National institute of Health, Bethesda, MD, USA.
⁷ Research and Development Institute, Transilvania University of Brasov, School of Medicine, Brasov, Romania.
⁸ Sloan Kettering Cancer Institute, New York, NY, USA.
⁹ FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. chsung@med.cornell.edu.
¹¹ Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. chsung@med.cornell.edu.

^# Contributed equally.

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Death
Chloride Channels / deficiency
Chloride Channels / genetics*
Disease Models, Animal
Fundus Oculi
Homeostasis
Lipid Metabolism
Macular Degeneration / diagnostic imaging
Macular Degeneration / genetics*
Macular Degeneration / physiopathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Proteins / deficiency
Mitochondrial Proteins / genetics*
Mutation / genetics*
Organ Specificity / genetics
Retinal Drusen / complications
Retinal Drusen / diagnostic imaging
Retinal Drusen / pathology
Retinal Pigment Epithelium / diagnostic imaging
Retinal Pigment Epithelium / metabolism*
Retinal Pigment Epithelium / physiopathology
Retinal Pigment Epithelium / ultrastructure
Risk Factors
Transcription, Genetic
Vision, Ocular / physiology

Substances

CLIC protein, mouse
Chloride Channels
Mitochondrial Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding