Correlation between Inactive Cathepsin D Expression and Retinal Changes in mcd2 / mcd2 Transgenic Mice

Zhang, Dan; Brankov, Meliha; Makhija, Mahindra T.; Robertson, Terry; Helmerhorst, Erik; Papadimitriou, John M.; Rakoczy, Piroska E.

doi:10.1167/iovs.04-1510

Cited by 23Retinal Development and DisordersRetinal Diseases and TreatmentsProtease and Inhibitor Mechanisms

Correlation between Inactive Cathepsin D Expression and Retinal Changes in mcd2 / mcd2 Transgenic Mice

Zhang, Dan, Brankov, Meliha, Makhija, Mahindra T., Robertson, Terry, Helmerhorst, Erik, Papadimitriou, John M., Rakoczy, Piroska E.·2005·Investigative Opthalmology & Visual Science

DOI 10.1167/iovs.04-1510

Open this paper in CoChat — free account

Abstract

PURPOSE: To investigate the correlation between the presence of the inactive cathepsin D (CatD) and retinal changes in mcd2/mcd2 transgenic mice. METHODS: Computational modeling was used to examine whether CatD mutants maintain competitive substrate binding. D407 cells were transfected with pcDNACatDM1 or pcDNACatDM2, containing procathepsin D (pro-CatD) with 6-bp (CatDM1) or 12-bp (CatDM2) deletions, respectively, flanking the pro-CatD cleavage site, and the aspartic protease activity of the transfected cells was measured. Subsequently, transgenic mice (mcd2/mcd2) containing CatDM2 were generated. Relative transgene copy number and transcript levels in the previously produced mcd/mcd (carrying CatDM1) and mcd2/mcd2 mice were measured by quantitative real-time PCR. Western blot analysis and aspartic protease activity were used to characterize the mutated proteins. Retinal changes were described by using color fundus photography and fluorescein angiography, histology, immunohistochemistry, and electron microscopy. RESULTS: Computational modeling of the CatDM1 and CatDM2 structures indicated that the substrate binding site was not altered. There was limited or no aspartic protease activity associated with CatDM1 and CatDM2 proteins, respectively. Mcd2/mcd2 animals contained a higher amount of inactive CatD than mcd/mcd or wild-type mice. Retinal abnormalities in mcd2/mcd2 mice developed at 3 months of age, earlier than in mcd/mcd mice. These changes included hypopigmentation, hyperfluorescence, retinal pigment epithelial (RPE) cell depigmentation or clumping, cell proliferation, and pleomorphism. Proliferating cells were identified as being of RPE origin. CONCLUSIONS: This study demonstrated a correlation between the presence of the inactive CatD in RPE cells and the development of ophthalmoscopic, cellular, and histologic changes in the retina.

Integrity signals

Registry

Crossref · 10.1167/iovs.04-1510

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Tight junctions and basal polarity of the RPE nucleus was lost in the mcd2/mcd2 mice.
“Tight junctions and basal polarity of the RPE nucleus was lost in the mcd2/mcd2 mice (Zhang et al., 2005).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Zhang et al., 2005
Three month-old mcd2/mcd2 mice showed focal areas of RPE disorganization, clumping, proliferation, and pleomorphism with attenuation, depigmentation, and atrophy.
“Three month-old mcd2/mcd2 mice showed focal areas of RPE disorganization, clumping, proliferation, and pleomorphism with attenuation, depigmentation, and atrophy.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Zhang et al., 2005
By 12 months old, almost all mcd2/mcd2 animals developed RPE proliferation.
“These early findings progressed with age, and by 12 months old almost all the animals developed RPE proliferation.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Zhang et al., 2005

SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling
Guex, N., & Peitsch, M. (1997) · Electrophoresis · doi:10.1002/elps.1150181505 · Cited by 11,589 · see citing works
SWISS-MODEL: an automated protein homology-modeling server
Schwede, T. F. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg520 · Cited by 5,592 · see citing works
An approach to computing electrostatic charges for molecules
Singh, U. C., & Kollman, P. A. (1984) · Journal of Computational Chemistry · doi:10.1002/jcc.540050204 · Cited by 3,495 · see citing works
Errors in protein structures
Hooft, R. W. W., Vriend, G., Sander, C., & Abola, E. E. (1996) · Nature · doi:10.1038/381272a0 · Cited by 2,180 · see citing works
Current concepts in the pathogenesis of age-related macular degeneration
Zarbin, M. A. (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.598 · Cited by 1,006 · see citing works
Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle
Redmond., T. M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., Ma, J.-X., Crouch, R. K., & Pfeifer, K. (1998) · Nature Genetics · doi:10.1038/3813 · Cited by 929 · see citing works
The Structure and Function of the Aspartic Proteinases
Davies, D. R. (1990) · Annual Review of Biophysics and Biophysical Chemistry · doi:10.1146/annurev.bb.19.060190.001201 · Cited by 658 · see citing works
The retinal pigment epithelium: a versatile partner in vision
Bok, D. (1993) · Journal of Cell Science · doi:10.1242/jcs.1993.supplement_17.27 · Cited by 593 · see citing works
The role of the retinal pigment epithelium: Topographical variation and ageing changes
Boulton, M., & Dayhaw‐Barker, P. (2001) · Eye · doi:10.1038/eye.2001.141 · Cited by 489 · see citing works
Retinal Pigment Epithelium
(2011) · SpringerReference · doi:10.1007/springerreference_36603 · Cited by 486 · see citing works
New trends in photobiology
Sarna, T. (1992) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/1011-1344(92)85027-r · Cited by 396 · see citing works
Cloning and sequence analysis of cDNA for human cathepsin D.
Faust, P. L., Kornfeld, S. A., & Chirgwin, J. M. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.15.4910 · Cited by 322 · see citing works
A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture.
Sparrow, J. R., Parish, C. A., Hashimoto, M., & Nakanishi, K. (1999) · PubMed · Cited by 312 · see citing works
The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium
Finnemann, S. C., Leung, L. W., & Rodriguez-Boulan, E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052025899 · Cited by 283 · see citing works
Aging-associated Changes in Human Brain
Mrak, R. E., Griffin, W. S. T., & Graham, D. I. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199712000-00001 · Cited by 229 · see citing works
Matrix and the retinal pigment epithelium in proliferative retinal disease
Hiscott, P. S., Sheridan, C., Magee, R. M., & Grierson, I. (1999) · Progress in Retinal and Eye Research · doi:10.1016/s1350-9462(98)00024-x · Cited by 223 · see citing works
Shedding of discs from rod outer segments in the rhesus monkey
Young, R. W. (1971) · Journal of Ultrastructure Research · doi:10.1016/s0022-5320(71)90014-1 · Cited by 206 · see citing works
Molecular genetics of Leber congenital amaurosis
Cremers, F. P. M. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.10.1169 · Cited by 200 · see citing works
Photocytotoxicity of lipofuscin in human retinal pigment epithelial cells
Davies, S., Elliott, M. H., Floor, E., Truscott, T. G., Zaręba, M., Sarna, T., Shamsi, F. A., & Boulton, M. E. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00582-2 · Cited by 198 · see citing works
Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies
Tchernof, A., & Labrie, F. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1510001 · Cited by 183 · see citing works
Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model
Rakoczy, P. E., Zhang, D., Robertson, T., Barnett, N. L., Papadimitriou, J., Constable, I. J., & Lai, C.-M. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64427-6 · Cited by 173 · see citing works
Self-citation
Processing of human cathepsin D in lysosomes in vitro.
Gieselmann, V., Hasilík, A., & FIGURA, K. V. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)89493-5 · Cited by 157 · see citing works
Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction
Bosch, E., Horwitz, J., & Bok, D. (1993) · Journal of Histochemistry & Cytochemistry · doi:10.1177/41.2.8419462 · Cited by 147 · see citing works
Outer Segments of Photoreceptors and the Retinal Pigment Epithelium
Spitznas, M. (1970) · Archives of Ophthalmology · doi:10.1001/archopht.1970.00990040812022 · Cited by 137 · see citing works
Untitled work
(2001) · PubMed · Cited by 136 · see citing works
Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin.
Shamsi, F. A., & Boulton, M. (2001) · PubMed · Cited by 130 · see citing works
Biosynthesis of lysosomal endopeptidases
Erickson, A. H. (1989) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240400104 · Cited by 129 · see citing works
The intercellular junctional complexes of retinal pigment epithelia.
Hudspeth, A. J., & Yee, A. G. (1973) · PubMed · Cited by 119 · see citing works
Update on the molecular genetics of retinitis pigmentosa
Wang, Q. K., Chen, Q., Zhao, K., Wang, L., Wang, L., & Traboulsi, E. I. (2001) · Ophthalmic Genetics · doi:10.1076/opge.22.3.133.2224 · Cited by 105 · see citing works
The high‐resolution crystal structure of porcine pepsinogen
Hartsuck, J. A., Koelsch, G., & Remington, S. J. (1992) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.340130102 · Cited by 93 · see citing works
Age-Dependent Iris Abnormalities in Collagen XVIII/Endostatin Deficient Mice with Similarities to Human Pigment Dispersion Syndrome
Marneros, A. G., & Olsen, B. R. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.02-1180 · Cited by 75 · see citing works
Regional variation and age-related changes of lysosomal enzymes in the human retinal pigment epithelium.
Boulton, M., Moriarty, P., Jarvis-Evans, J., & Marcyniuk, B. (1994) · British Journal of Ophthalmology · doi:10.1136/bjo.78.2.125 · Cited by 74 · see citing works
Modulation of cathepsin D activity in retinal pigment epithelial cells
RAKOCZY, P. E., LAI, C. M., BAINES, M., GRANDI, S. D., FITTON, J. H., & CONSTABLE, I. J. (1997) · Biochemical Journal · doi:10.1042/bj3240935 · Cited by 64 · see citing works
Effects of cysteine protease inhibitors on rabbit cathepsin D maturation
Samarel, A. M., Ferguson, A. G., Decker, R. S., & Lesch, M. (1989) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1989.257.6.c1069 · Cited by 62 · see citing works
Degradation of rhodopsin by a lysosomal fraction of retinal pigment epithelium: Biochemical aspects of the visual process. XLI
Regan, C. M., de Grip, W. J., Daemen, F. J. M., & Bonting, S. L. (1980) · Experimental Eye Research · doi:10.1016/0014-4835(80)90112-8 · Cited by 60 · see citing works
A2E and Blue Light in the Retina: The Paradigm of Age-Related Macular Degeneration
Shaban, H., & Richter, C. (2002) · Biological Chemistry · doi:10.1515/bc.2002.054 · Cited by 57 · see citing works
Fluorescent pigments of the retinal pigment epithelium and age-related macular degeneration
Ben‐Shabat, S., Parish, C. A., Hashimoto, M., Liu, J., Nakanishi, K., & Sparrow, J. R. (2001) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(01)00314-6 · Cited by 57 · see citing works
Correlation between autofluorescent debris accumulation and the presence of partially processed forms of cathepsin D in cultured retinal pigment epithelial cells challenged with rod outer segments
RAKOCZY, P. E., BAINES, M., KENNEDY, C. J., & CONSTABLE, I. J. (1996) · Experimental Eye Research · doi:10.1006/exer.1996.0104 · Cited by 43 · cited 1× · see citing works
“3 14 11/14 (79) 7/14 (50) 6/14 (42) 0/14 (0) 0/14 (0) 6 16 14/16 (88) 9/16 (56) 8/16 (50) 3/16 ( 19 ) 8/16 (50) 12 16 15/16 (94) 11/16 (69) 10/16 (63) 6/16 (38) 14/16 (88)”
Self-citation
Accumulation of inactive cathepsin D in old rats
Wiederanders, B., & Oelke, B. (1984) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(84)90112-x · Cited by 40 · see citing works
Genetic Animal Models for Retinal Degeneration
Fauser, S., Luberichs, J., & Schüttauf, F. (2002) · Survey of Ophthalmology · doi:10.1016/s0039-6257(02)00314-4 · Cited by 34 · see citing works
Pathophysiology of type 2 Diabetes in the Elderly
Meneilly, G. S. (1999) · Clinics in Geriatric Medicine · doi:10.1016/s0749-0690(18)30057-0 · Cited by 28 · see citing works
Vectorial accumulation of cathepsin D in retinal pigmented epithelium: effects of age.
Wilcox, D. K. (1988) · PubMed · Cited by 20 · see citing works
A model for a blinding eye disease of the aged
Zhang, D., Lai, M. C., Constable, I. J., & Rakoczy, P. E. (2002) · Biogerontology · doi:10.1023/a:1015259413857 · Cited by 16 · see citing works
Self-citation

Flagged first, then by citations

Sorted by citations

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents
Travis, G. H., Golczak, M., Moise, A. R., & Palczewski, K. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105225 · Cited by 419 · see citing works
Animal models of age related macular degeneration
Pennesi, M. E., Neuringer, M., & Courtney, R. J. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.06.003 · Cited by 391 · see citing works
Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)
Ramkumar, H. L., Zhang, J., & Chan, C.-C. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.02.002 · Cited by 163 · see citing works
Understanding the structure–function role of specific catalytic residues in a model food related enzyme: Pepsin
Sinkovits, A. F., Bryksa, B. C., Tanaka, T., & Yada, R. Y. (2007) · Enzyme and Microbial Technology · doi:10.1016/j.enzmictec.2006.08.029 · Cited by 16 · see citing works

Early Changes in Behavior Deficits, Amyloid β-42 Deposits and MAPK Activation in Doubly Transgenic Mice Co-expressing NSE-Controlled Human Mutant PS2 and APPsw
Hwang, D. Y., Cho, J. S., Oh, J. H., Shim, S. B., Jee, S. W., Lee, S. H., Seo, S. J., Song, C. W., Lee, S. H., & Kim, Y. K. (2005) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-005-4950-x · Cited by 6 · see citing works
Development and Characterization of Thy*IκBα-SI Transgenic Mice
Gushchina, S. V., Michael, G., Volkova, O. V., et al. (2010) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-010-1120-z · Cited by 1 · see citing works
Transgenic mice: beyond the knockout
Miller, R. L. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00082.2010 · Cited by 25 · see citing works
[Transgenic mice in basic research].
Gassmann, M., Hennet, T., & Bauer, C. (1998) · PubMed · Cited by 1 · see citing works
In vivo expression of a conditional TGF-β1 transgene: no evidence for TGF-β1 transgene expression in SM22α-tTA transgenic mice
Lee, S., Agah, R., Xiao, M., et al. (2005) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2005.09.015 · Cited by 8 · see citing works

Authors: Zhang, D., Brankov, M., Makhija, M. T., Robertson, T., Helmerhorst, E., Papadimitriou, J. M., & Rakoczy, P. E.
Affiliations: Lions Eye Institute (AU)
Curtin University (AU)
Department of Pathology and
ORCID: Zhang, Dan
Venue: Investigative Opthalmology & Visual Science
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Published: 2005-09-01
Volume: 46
Issue: 9
Pages: 3031
ISSN: 0146-0404 (ISSN-L)
1552-5783
DOI: 10.1167/iovs.04-1510
OpenAlex: W2043851993
Cited by: 23
References: 43
Citations by year: 2026: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 2
FWCI: 0.75
Type: journal article
Language: en
Open access: closed
Locations: Investigative Ophthalmology & Visual Science (publishedVersion, public-domain)
PubMed (publishedVersion)
UWA Profiles and Research Repository (UWA) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: retinal changes, retinal pigment epithelium, substrate binding site, retinal degeneration
MeSH terms: Animals, Cathepsin D, Computer Simulation, Enzyme Precursors, Fluorescein Angiography, Humans, Immunohistochemistry, Macular Degeneration, Mice, Inbred C57BL, Mice, Transgenic, Pigment Epithelium of Eye, Transfection, Blotting, Western, Molecular Structure, Aspartic Acid Endopeptidases, Gene Deletion, Reverse Transcriptase Polymerase Chain Reaction, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Correlation between Inactive Cathepsin D Expression and Retinal Changes in mcd2 / mcd2 Transgenic Mice

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks