Compromised phagosome maturation underlies RPE pathology in cell culture and whole animal models of Smith-Lemli-Opitz Syndrome
Open accessAbstract
Treatment of rats with the cholesterol pathway inhibitor AY9944 produces an animal model of Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive disease caused by defective cholesterol synthesis. This SLOS rat model undergoes progressive and irreversible degeneration of the neural retina, with associated pathological features of the retinal pigmented epithelium (RPE). Here, we provide further insights into the mechanism involved in the RPE pathology. In the SLOS rat model, markedly increased RPE apical autofluorescence is observed, compared to untreated animals, which correlates with increased levels of A2E and other bisretinoids. Utilizing cultured human induced pluripotent stem cell (iPSC)- derived SLOS RPE cells, we found significantly elevated steady-state levels of 7-dehydrocholesterol (7DHC) and decreased cholesterol levels (key biochemical hallmarks of SLOS). Western blot analysis revealed altered levels of the macroautophagy/autophagy markers MAP1LC3B-II and SQSTM1/p62, and build-up of ubiquitinated proteins. Accumulation of immature autophagosomes was accompanied by inefficient degradation of phagocytized, exogenously supplied retinal rod outer segments (as evidenced by persistence of the C-terminal 1D4 epitope of RHO [rhodopsin]) in SLOS RPE compared to iPSC-derived normal human control. SLOS RPE cells exhibited lysosomal pH levels and CTSD activity within normal physiological limits, thus discounting the involvement of perturbed lysosomal function. Furthermore, 1D4-positive phagosomes that accumulated in the RPE in both pharmacological and genetic rodent models of SLOS failed to fuse with lysosomes. Taken together, these observations suggest that defective phagosome maturation underlies the observed RPE pathology. The potential relevance of these findings to SLOS and the requirement of cholesterol for phagosome maturation are discussed.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Impaired autophagy in these diseases is accompanied by defects in other organelles/functions such as delayed phagosome maturation, lysosomal dysfunction, and endosomal abnormalities.
“Impaired autophagy is accompanied by defects in other organelles/functions such as delayed phagosome maturation (Bietti’s, Batten, SLO (Wavre-Shapton et al., 2015; Hata et al., 2018; Ramachandra Rao et al., 2018)), lysosomal dysfunction (Stargardt, Batten, Bietti’s (Liu et al., 2008; Wavre-Shapton et al., 2015; Tan et al., 2016; Hata et al., 2018)), and endosomal abnormalities (Stargardt (Kaur et”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Ramachandra Rao et al., 2018
In Batten, Bietti's, and SLO diseases, autophagic defects manifest as an accumulation of LC3-positive autophagosomes and increased p62, suggestive of a block in autophagosome-lysosome fusion.
“In Abca4−/− RPE, both autophagosome biogenesis and autophagic flux are inhibited (Toops et al., 2015); however, in Batten, Bietti’s, and SLO diseases, autophagic defects manifest as an accumulation of LC3-positive autophagosomes and increased p62, suggestive of a block in autophagosome-lysosome fusion.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Ramachandra Rao et al., 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega
Sievers, F., Wilm, A., Dineen, D., Gibson, T., Karplus, K., Li, W.-Z., Lopez, R., McWilliam, H., Remmert, M., Söding, J., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.75 · Cited by 15,576 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Cui, C., Cui, J., Jin, F., Cui, Y., Li, R., Jiang, X., Tian, Y., Wang, R. C., Jiang, P., & Gao, J. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479571 · Cited by 5,214 · see citing works
Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702824200 · Cited by 4,578 · see citing works
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Øvervatn, A., Stenmark, H., & Johansen, T. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200507002 · Cited by 3,276 · see citing works
Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells
Ikeda, R., Che, X., Yamaguchi, T., Ushiyama, M., Zheng, C., Okumura, H., Takeda, Y., Shibayama, Y., Nakamura, K. T., Jeung, H., et al. (2005) · Cancer Science · doi:10.1111/j.1349-7006.2005.00057.x · Cited by 2,268 · see citing works
The machinery of macroautophagy
Feng, Y., He, D., Yao, Z., & Klionsky, D. J. (2014) · Cell Research · doi:10.1038/cr.2013.168 · Cited by 2,083 · see citing works
The role of autophagy in neurodegenerative disease
Nixon, R. A. (2013) · Nature Medicine · doi:10.1038/nm.3232 · Cited by 2,059 · see citing works
Tanida, I., Ueno, T., & Kominami, E. (2008) · Methods in Molecular Biology™ · doi:10.1007/978-1-59745-157-4_4 · Cited by 1,785 · see citing works
Seglen, P. O., & Gordon, P. B. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.6.1889 · Cited by 1,360 · see citing works
The Atg12-Atg5 Conjugate Has a Novel E3-like Activity for Protein Lipidation in Autophagy
Hanada, T., Noda, N. N., Satomi, Y., Ichimura, Y., Fujioka, Y., Takao, T., Inagaki, F., & Ohsumi, Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c700195200 · Cited by 1,123 · see citing works
Cholesterol, lipid rafts, and disease
Simons, K., & Ehehalt, R. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16390 · Cited by 995 · see citing works
Cholesterol, lipid rafts, and disease
Simons, K., & Ehehalt, R. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0216390 · Cited by 916 · see citing works
Autophagy gone awry in neurodegenerative diseases
Wong, E. S. P., & Cuervo, A. M. (2010) · Nature Neuroscience · doi:10.1038/nn.2575 · Cited by 883 · see citing works
Chaperone-mediated autophagy: roles in disease and aging
Cuervo, A. M., & Wong, E. S. P. (2013) · Cell Research · doi:10.1038/cr.2013.153 · Cited by 850 · see citing works
Autophagy: assays and artifacts
Barth, S., Glick, D. R., & Macleod, K. F. (2010) · The Journal of Pathology · doi:10.1002/path.2694 · Cited by 794 · see citing works
Rocha, N., Kuijl, C. P., van der Kant, R., Janssen, L., Houben, D., Janssen, H., Zwart, W. T., & Neefjes, J. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200811005 · Cited by 705 · see citing works
Gal, A., Li, Y., Thompson, D. A., Weir, J., Orth, U., Jacobson, S. G., Apfelstedt-Sylla, E., & Vollrath, D. (2000) · Nature Genetics · doi:10.1038/81555 · Cited by 679 · see citing works
Phagosome maturation: aging gracefully
Vieira, O. V., Botelho, R. J., & Grinstein, S. (2002) · Biochemical Journal · doi:10.1042/bj20020691 · Cited by 675 · see citing works
A newly recognized syndromeof multiple congenital anomalies
Smith, D. W., Lemli, L., & Opitz, J. M. (1964) · The Journal of Pediatrics · doi:10.1016/s0022-3476(64)80264-x · Cited by 650 · see citing works
RPE lipofuscin and its role in retinal pathobiology
Sparrow, J. R., & Boulton, M. (2005) · Experimental Eye Research · doi:10.1016/j.exer.2005.01.007 · Cited by 644 · see citing works
A solvent system for delipidation of plasma or serum without protein precipitation
Cham, B. E., & Knowles, B. R. (1976) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37003-6 · Cited by 515 · see citing works
Terman, A., Kurz, T., Navratil, M., Arriaga, E. A., & Brunk, U. T. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2598 · Cited by 490 · see citing works
Marmorstein, A. D., Marmorstein, L. Y., Rayborn, M. E., Wang, X., Hollyfield, J. G., & Petrukhin, K. E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.220402097 · Cited by 456 · see citing works
Mitter, S. K., Song, C., Qi, X., Mao, H., Rao, H., Akin, D., Lewin, A., Grant, M., Dunn, W., Ding, J., et al. (2014) · Autophagy · doi:10.4161/auto.36184 · Cited by 449 · see citing works
Altered lipid content inhibits autophagic vesicular fusion
Koga, H., Kaushik, S., & Cuervo, A. M. (2010) · The FASEB Journal · doi:10.1096/fj.09-144519 · Cited by 429 · see citing works
Maminishkis, A., Chen, S., Jalickee, S., Banzon, T., Shi, G., Wang, F. E., Ehalt, T., Hammer, J. A., & Miller, S. S. (2006) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.05-1622 · Cited by 401 · see citing works
Rafts: Scale‐Dependent, Active Lipid Organization at the Cell Surface
Mayor, S., & Rao, M. (2004) · Traffic · doi:10.1111/j.1600-0854.2004.00172.x · Cited by 379 · see citing works
Sahani, M. H., Itakura, E., & Mizushima, N. (2014) · Autophagy · doi:10.4161/auto.27344 · Cited by 363 · see citing works
Noncanonical autophagy promotes the visual cycle
Kim, J.-Y., Zhao, H., Martinez, J., Doggett, T. A., Kolesnikov, A. V., Tang, P. H., Ablonczy, Z., Chan, C.-C., Zhou, Z., Green, D. R., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.012 · Cited by 347 · see citing works
Autophagy in cardiovascular biology
Lavandero, S., Chiong, M., Rothermel, B. A., & Hill, J. A. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73943 · Cited by 331 · see citing works
The life cycle of phagosomes: formation, maturation, and resolution
Levin‐Konigsberg, R., Grinstein, S., & Canton, J. (2016) · Immunological Reviews · doi:10.1111/imr.12439 · Cited by 307 · see citing works
Impaired Autophagy in the Lipid-Storage Disorder Niemann-Pick Type C1 Disease
Sarkar, S., Carroll, B., Buganim, Y., Maetzel, D., Ng, A. H. M., Cassady, J. P., Cohen, M. A., Chakraborty, S., Wang, H., Spooner, E., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.10.042 · Cited by 290 · see citing works
PARTICIPATION OF THE RETINAL PIGMENT EPITHELIUM IN THE ROD OUTER SEGMENT RENEWAL PROCESS
Young, R. W., & Bok, D. (1969) · Journal of Cell Biology · doi:10.1083/jcb.42.2.392 · Cited by 271 · see citing works
Liu, J., Itagaki, Y., Ben-Shabat, S., Nakanishi, K., & Sparrow, J. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910191199 · Cited by 255 · see citing works
Saari, J. C., Nawrot, M., Kennedy, B. N., Garwin, G. G., Hurley, J. B., Huang, J., Possin, D. E., & Crabb, J. W. (2001) · Neuron · doi:10.1016/s0896-6273(01)00248-3 · Cited by 250 · see citing works
Ferrington, D. A., Sinha, D., & Kaarniranta, K. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2015.09.002 · Cited by 241 · see citing works
Wijdeven, R. H. M., Janssen, H., Nahidiazar, L., Janssen, L., Jalink, K., Berlin, I., & Neefjes, J. (2016) · Nature Communications · doi:10.1038/ncomms11808 · Cited by 230 · see citing works
Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay
Kim, M., Sandford, E., Gatica, D., Qiu, Y., Liu, X., Zheng, Y., Schulman, B. A., Xu, J., Semple, I., Ro, S.-H., et al. (2016) · eLife · doi:10.7554/elife.12245 · Cited by 225 · see citing works
Yoon, Y. H., Cho, K. S., Hwang, J. J., Lee, S.-J., Choi, J. A., & Koh, J.-Y. (2010) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.10-5278 · Cited by 219 · see citing works
Dynein Clusters into Lipid Microdomains on Phagosomes to Drive Rapid Transport toward Lysosomes
Rai, A., Pathak, D., Thakur, S., Singh, S., Dubey, A. K., & Mallik, R. (2016) · Cell · doi:10.1016/j.cell.2015.12.054 · Cited by 206 · see citing works
Acetylated microtubules are required for fusion of autophagosomes with lysosomes
Xie, R., Nguyen, S., McKeehan, W. L., & Liu, L. (2010) · BMC Cell Biology · doi:10.1186/1471-2121-11-89 · Cited by 203 · see citing works
Witsch‐Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H. H., Seedorf, U., Gillessen‐Kaesbach, G., Hoffmann, G. F., Clayton, P. T., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/302760 · Cited by 188 · see citing works
Saini, J. S., Corneo, B., Miller, J. D., Kiehl, T. R., Wang, Q., Boles, N. C., Blenkinsop, T. A., Stern, J. H., & Temple, S. (2017) · Cell stem cell · doi:10.1016/j.stem.2016.12.015 · Cited by 187 · see citing works
Coffey, E. E., Beckel, J. M., Laties, A. M., & Mitchell, C. H. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.01.001 · Cited by 183 · see citing works
Tserentsoodol, N., Sztein, J., Campos, M. M., Gordiyenko, N., Fariss, R. N., Lee, J. W., Fliesler, S. J., & Rodríguez, I. R. (2006) · PubMed · Cited by 176 · see citing works
Untangling Autophagy Measurements
Gottlieb, R. A., Andres, A. M., Sin, J., & TAYLOR, D. J. (2015) · Circulation Research · doi:10.1161/circresaha.116.303787 · Cited by 170 · see citing works
The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells
Lakkaraju, A., Finnemann, S. C., & Rodriguez-Boulan, E. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702504104 · Cited by 162 · see citing works
Retinal Pigment Epithelium Lipofuscin Proteomics
Ng, K.-P., Gugiu, B., Renganathan, K., Davies, M. W., Gu, X., Crabb, J. S., Kim, S. R., Różanowska, M. B., Bonilha, V. L., Rayborn, M. E., et al. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m700525-mcp200 · Cited by 162 · see citing works
Marmorstein, A. D., Marmorstein, L. Y., Sakaguchi, H., & Hollyfield, J. G. (2002) · PubMed · Cited by 154 · see citing works
Xu, L., Korade, Ž., & Porter, N. A. (2010) · Journal of the American Chemical Society · doi:10.1021/ja9080265 · Cited by 154 · see citing works
Impaired proteolysis underlies autophagic dysfunction in Niemann–Pick type C disease
Elrick, M. J., Yu, T., Chung, C., & Lieberman, A. P. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds324 · Cited by 148 · 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
Treatment of Smith-Lemli-Opitz syndrome: Results of a multicenter trial
Irons, M., Elias, E. R., Abuelo, D. N., Bull, M. J., Greene, C. L., Johnson, V. P., Keppen, L. D., Schanen, C., Tint, G. S., & Salen, G. (1997) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19970131)68:3 · Cited by 138 · see citing works
Shefer, S., Salen, G., Batta, A. K., Honda, A., Tint, G. S., Irons, M., Elias, E. R., Chen, T. C., & Holick, M. F. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118223 · Cited by 138 · see citing works
Autophagy in the eye: implications for ocular cell health.
Frost, L. S., Mitchell, C. H., & Boesze-Battaglia, K. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2014.04.010 · Cited by 134 · see citing works
Baltazar, G. C., Guha, S., Lu, W., Lim, J. C.-S., Boesze‐Battaglia, K., Laties, A. M., Tyagi, P., Kompella, U. B., & Mitchell, C. H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049635 · Cited by 133 · see citing works
Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link
Tricarico, P. M., Crovella, S., & Celsi, F. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160716067 · Cited by 131 · see citing works
Internalized gap junctions are degraded by autophagy
Fong, J. T., Kells, R. M., Gumpert, A. M., Marzillier, J. Y., Davidson, M. W., & Falk, M. M. (2012) · Autophagy · doi:10.4161/auto.19390 · Cited by 117 · see citing works
CHILD syndrome caused by deficiency of 3?-hydroxysteroid-?8, ?7-isomerase
Grange, D. K., Kratz, L. E., Braverman, N., & Kelley, R. I. (2000) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(20000214)90:4 · Cited by 113 · see citing works
Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification
Cox, B. E., Griffin, E. E., Ullery, J. C., & W. Gray, J. (2007) · Journal of Lipid Research · doi:10.1194/jlr.m600390-jlr200 · Cited by 110 · see citing works
Xu, L., Korade, Ž., Rosado, J. D. A., Liu, W. X., Lamberson, C. R., & Porter, N. A. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m014498 · Cited by 109 · see citing works
Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy
Mahon, G. J., Anderson, H. R., Gardiner, T. A., McFarlane, S., Archer, D. B., & Stitt, A. W. (2004) · Current Eye Research · doi:10.1076/ceyr.28.4.277.27835 · Cited by 108 · see citing works
Toops, K. A., Tan, L. X., Jiang, Z., Radu, R. A., & Lakkaraju, A. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-05-1028 · Cited by 105 · see citing works
Gordiyenko, N. V., Campos, M. M., Lee, J. W., Fariss, R. N., Sztein, J., & Rodríguez, I. R. (2004) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.04-0074 · Cited by 102 · see citing works
Miyagishima, K. J., Wan, Q., Corneo, B., Sharma, R., Lotfi, M., Boles, N. C., Hua, F., Maminishkis, A., Zhang, C., Blenkinsop, T. A., et al. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2016-0037 · Cited by 102 · see citing works
Brandl, C., Zimmermann, S. J., Milenkovic, V. M., Rosendahl, S. M. G., Graßmann, F., Milenkovic, A., Hehr, U., Federlin, M., Wetzel, C. H., Helbig, H., et al. (2014) · NeuroMolecular Medicine · doi:10.1007/s12017-014-8308-8 · Cited by 92 · see citing works
Yu, H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.9.1385 · Cited by 90 · see citing works
Cholesterol Accumulation by Macrophages Impairs Phagosome Maturation
Huynh, K. K., Gershenzon, E., & Grinstein, S. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806232200 · Cited by 89 · see citing works
Lysosomes: regulators of autophagy in the retinal pigmented epithelium
Sinha, D., Valapala, M., Shang, P., Hose, S., Grebe, R., Lutty, G. A., Zigler, J. S., Kaarniranta, K., & Handa, J. T. (2016) · Experimental Eye Research · doi:10.1016/j.exer.2015.08.018 · Cited by 88 · see citing works
Chapter 10 Improved methodology for cell culture of human and monkey retinal pigment epithelium
Pfeffer, B. A. (1991) · Progress in Retinal Research · doi:10.1016/0278-4327(91)90015-t · Cited by 85 · see citing works
Macrophages Rapidly Transfer Pathogens from Lipid Raft Vacuoles to Autophagosomes
Amer, A. O., Byrne, B. G., & Swanson, M. S. (2005) · Autophagy · doi:10.4161/auto.1.1.1589 · Cited by 82 · see citing works
Brandstaetter, H., Kishi‐Itakura, C., Tumbarello, D. A., Manstein, D. J., & Buß, F. (2014) · Autophagy · doi:10.4161/15548627.2014.984272 · Cited by 82 · see citing works
p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium.
Wang, L., Cano, M., & Handa, J. T. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.03.016 · Cited by 82 · see citing works
Guha, S., Coffey, E. E., Lu, W., Lim, J. C.-S., Beckel, J. M., Laties, A. M., Boesze‐Battaglia, K., & Mitchell, C. H. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2014.05.013 · Cited by 81 · see citing works
Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy
Miettinen, T. P., & Björklund, M. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.11.045 · Cited by 79 · see citing works
Francis, K. R., Ton, A. N., Xin, Y., O'Halloran, P. E., Wassif, C. A., Malik, N., Williams, I. M., Cluzeau, C. V. M., Trivedi, N. S., Pavan, W. J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4067 · Cited by 79 · see citing works
Honda, A., Tint, G. S., Salen, G., Batta, A. K., Chen, T. S., & Shefer, S. (1995) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39745-5 · Cited by 79 · see citing works
Lack of Niemann-Pick type C1 induces age-related degeneration in the mouse retina
Claudepierre, T., Paques, M., Simonutti, M., Buard, I., Sahel, J., Maue, R. A., Picaud, S., & Pfrieger, F. W. (2010) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2009.10.007 · Cited by 77 · see citing works
Correa-Cerro, L. S., Wassif, C. A., Kratz, L., Miller, G. F., Munasinghe, J. P., Grinberg, A., Fliesler, S. J., & Porter, F. D. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl003 · Cited by 75 · see citing works
Self-citationXu, L., Liu, W. X., Sheflin, L. G., Fliesler, S. J., & Porter, N. A. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m018366 · Cited by 74 · see citing works
Muniz-Feliciano, L., Doggett, T. A., Zhou, Z., & Ferguson, T. A. (2017) · Autophagy · doi:10.1080/15548627.2017.1380124 · Cited by 73 · see citing works
Ocular Manifestations of the Smith-Lemli-Opitz Syndrome
Kretzer, F. L., Hittner, H. M., & Mehta, R. S. (1981) · Archives of Ophthalmology · doi:10.1001/archopht.1981.03930020876013 · Cited by 72 · see citing works
Wassif, C. A., Krakowiak, P. A., Wright, B. S., Gewandter, J. S., Sterner, A. L., Javitt, N. B., Yergey, A. L., & Porter, F. D. (2005) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2004.12.009 · Cited by 64 · see citing works
Retinal Degeneration in a Rodent Model of Smith-Lemli-Opitz Syndrome
Fliesler, S. J. (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.8.1190 · Cited by 64 · see citing works
Frost, L. S., Lopes, V. S., Bragin, A., Reyes-Reveles, J., Brancato, J., Cohen, A., Mitchell, C. H., Williams, D. S., & Boesze-Battaglia, K. (2015) · Molecular Neurobiology · doi:10.1007/s12035-014-8920-5 · Cited by 63 · see citing works
Self-citationAutophagy and phagocytosis converge for better vision
Ferguson, T. A., & Green, D. R. (2013) · Autophagy · doi:10.4161/auto.26735 · Cited by 62 · see citing works
Kellner, U., Kellner, S., & Weinitz, S. (2007) · Documenta Ophthalmologica · doi:10.1007/s10633-007-9105-6 · Cited by 60 · see citing works
Wavre-Shapton, S. T., Meschede, I. P., Seabra, M. C., & Futter, C. E. (2014) · Journal of Cell Science · doi:10.1242/jcs.154757 · Cited by 60 · see citing works
Tricarico, P. M., Romeo, A., Gratton, R., Crovella, S., & Celsi, F. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000471235 · Cited by 60 · see citing works
Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells
Xu, L., Korade, Ž., Rosado, D. A., Mirnics, K., & Porter, N. A. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m035733 · Cited by 59 · see citing works
Acidification of phagosomes and degradation of rod outer segments in rat retinal pigment epithelium.
Deguchi, J., Yamamoto, A., Yoshimori, T., Sugasawa, K., Moriyama, Y., Futai, M., Suzuki, T., Kato, K., Uyama, M., & Tashiro, Y. (1994) · PubMed · Cited by 57 · see citing works
Ion-current-based Proteomic Profiling of the Retina in a Rat Model of Smith-Lemli-Opitz Syndrome
Tu, C., Li, J., Jiang, X.-S., Sheflin, L. G., Pfeffer, B. A., Behringer, M. D., Fliesler, S. J., & Qu, J. (2013) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.027847 · Cited by 54 · see citing works
Crouch, R. K., Koutalos, Y., Kono, M., Schey, K. L., & Ablonczy, Z. (2015) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2015.06.005 · Cited by 53 · see citing works
A Novel Bisretinoid of Retina Is an Adduct on Glycerophosphoethanolamine
Yamamoto, K., Yoon, K. D., Ueda, K., Hashimoto, M., & Sparrow, J. R. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-8632 · Cited by 53 · see citing works
Xu, L., Sheflin, L. G., Porter, N. A., & Fliesler, S. J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.03.001 · Cited by 53 · see citing works
Cholesterol storage defect in RSH/Smith–Lemli–Opitz syndrome fibroblasts
Wassif, C. A., Vied, D., Tsokos, M., Connor, W. E., Steiner, R. D., & Porter, F. D. (2002) · Molecular Genetics and Metabolism · doi:10.1016/s1096-7192(02)00010-0 · Cited by 52 · see citing works
Ferrer, M., Corneo, B., Davis, J. A., Wan, Q., Miyagishima, K. J., King, R., Maminishkis, A., Marugán, J., Sharma, R., Shure, M. S., et al. (2014) · Stem Cells Translational Medicine · doi:10.5966/sctm.2013-0192 · Cited by 52 · see citing works
Ford, D. A., Monda, J. K., Brush, R. S., Anderson, R. E., Richards, M. J., & Fliesler, S. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05203.x · Cited by 49 · see citing works
Ishibashi, S., Yamazaki, T., & Okamoto, K. (2009) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2008.09.020 · Cited by 44 · see citing works
Saadat, K. A. S. M., Murakami, Y., Tan, X., Nomura, Y., Yasukawa, T., Okada, E., Ikeda, Y., & Yanagi, Y. (2014) · FEBS Open Bio · doi:10.1016/j.fob.2014.11.003 · Cited by 44 · see citing works
Pfeffer, B. A., Xu, L., Porter, N. A., Rao, S. R., & Fliesler, S. J. (2016) · Experimental Eye Research · doi:10.1016/j.exer.2016.01.016 · Cited by 44 · see citing works
Hoppe, G., O'Neil, J., Hoff, H., & Sears, J. E. (2004) · Cellular and Molecular Life Sciences (CMLS) · doi:10.1007/s00018-004-4080-5 · Cited by 42 · see citing works
Lei, L., Tzekov, R. T., Li, H., McDowell, J. H., Gao, G., Smith, W. C., Tang, S., & Kaushal, S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040728 · Cited by 41 · see citing works
Outer segment disc shedding and phagocytosis in the outer retina.
Mm, L. (1983) · PubMed · Cited by 40 · see citing works
The Role of IRE-XBP1 Pathway in Regulation of Retinal Pigment Epithelium Tight Junctions
Ma, J. H., Wang, J. J., Li, J., Pfeffer, B. A., Zhong, Y., & Zhang, S. X. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.16-19232 · Cited by 40 · see citing works
Fliesler, S. J., Richards, M. J., Miller, C., & Peachey, N. S. (1999) · PubMed · Cited by 37 · see citing works
Punnonen, E.-L., Pihakaski, K., Mattila, K., Lounatmaa, K., & Hirsim�ki, P. (1989) · Cell and Tissue Research · doi:10.1007/bf00239447 · Cited by 37 · see citing works
New cellular mechanisms of gap junction degradation and recycling
Carette, D., Gilleron, J., Denizot, J., Grant, K., Pointis, G., & Segretain, D. (2015) · Biology of the Cell · doi:10.1111/boc.201400048 · Cited by 34 · see citing works
Pfeffer, B. A., Becerra, S. P., Borst, D. E., & WONG, P. W. K. (2004) · PubMed · Cited by 34 · see citing works
Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome
Fliesler, S. J., Peachey, N. S., Herron, J. M., Hines, K. M., Weinstock, N. I., Rao, S. R., & Xu, L. (2018) · Scientific Reports · doi:10.1038/s41598-018-19592-8 · Cited by 33 · see citing works
Marcos, J., Shackleton, C. H. L., Buddhikot, M., Porter, F. D., & Watson, G. L. (2007) · Steroids · doi:10.1016/j.steroids.2007.07.002 · Cited by 31 · see citing works
Caldwell, R. B., & McLaughlin, B. J. (1985) · The Journal of Comparative Neurology · doi:10.1002/cne.902360408 · Cited by 29 · see citing works
Boesze‐Battaglia, K., Damek-Poprawa, M., Mitchell, D. C., Greeley, L. A., Brush, R. S., Anderson, R. E., Richards, M. J., & Fliesler, S. J. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800031-jlr200 · Cited by 29 · see citing works
Silvestri, G., Rana, M., Odoardi, F., Modoni, A., Paris, E., Papacci, M., Tonali, P., & Servidei, S. (2000) · American Journal of Medical Genetics · doi:10.1002/1096-8628(20000918)94:3 · Cited by 25 · see citing works
Antioxidants: The Missing Key to Improved Therapeutic Intervention in Smith-Lemli-Opitz Syndrome
Fliesler, S. J. (2013) · Hereditary Genetics · doi:10.4172/2161-1041.1000119 · Cited by 23 · see citing works
In vivo and in vitro monitoring of phagosome maturation in retinal pigment epithelium cells
Esteve-Rudd, J., Lopes, V. S., Jiang, M., & Williams, D. S. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3209-8_11 · Cited by 22 · see citing works
Elevated autophagy and mitochondrial dysfunction in the Smith–Lemli–Opitz Syndrome
Chang, S., Ren, G., Steiner, R. D., Merkens, L. S., Roullet, J., Korade, Ž., DiMuzio, P. J., & Tulenko, T. N. (2014) · Molecular Genetics and Metabolism Reports · doi:10.1016/j.ymgmr.2014.09.005 · Cited by 21 · see citing works
Bloch, K. E. (1989) · Steroids · doi:10.1016/0039-128x(89)90014-7 · Cited by 20 · see citing works
Cone ERG responses in patients with Smith-Lemli-Opitz Syndrome (SLOS)
Garry, D., Hansen, R. M., Moskowitz, A., Elias, E. R., Irons, M., & Fulton, A. B. (2010) · Documenta Ophthalmologica · doi:10.1007/s10633-010-9232-3 · Cited by 19 · see citing works
The Bisretinoids of RPE Lipofuscin: A Complex Mixture
Sparrow, J. R., & Yamamoto, K. (2012) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4614-0631-0_97 · Cited by 15 · see citing works
Ying, L., Matabosch, X., Serra, M., Watson, B., Shackleton, C. H. L., & Watson, G. L. (2014) · Molecular Genetics and Metabolism Reports · doi:10.1016/j.ymgmr.2014.02.002 · Cited by 12 · see citing works
Experimental Chloroquine Retinopathy
Matsumura, M., OHKUMA, M., & Tsukahara, I. (2009) · Ophthalmic Research · doi:10.1159/000265429 · Cited by 11 · see citing works
Hepatic Isoprenoid Metabolism in a Rat Model of Smith‐Lemli‐Opitz Syndrome
Keller, R. K., Mitchell, D. A., Goulah, C. C., & Fliesler, S. J. (2013) · Lipids · doi:10.1007/s11745-013-3762-x · Cited by 7 · see citing works
Retinal Degeneration and Cholesterol Deficiency
Fliesler, S. J. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-401717-7.00029-0 · Cited by 6 · see citing works
Flagged first, then by citations
1 of the 130 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationMechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration
Kaarniranta, K., Uusitalo, H. M. T., Błasiak, J., Felszeghy, S., Kannan, R., Kauppinen, A., Salminen, A., Sinha, D., & Ferrington, D. A. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100858 · Cited by 528 · see citing works
The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422 · see citing works
Bharti, K., den Hollander, A. I., Lakkaraju, A., Sinha, D., Williams, D. S., Finnemann, S. C., Rickman, C. B., Malek, G., & D'Amore, P. A. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2022.109170 · Cited by 92 · see citing works
Cholesterol homeostasis in the vertebrate retina: biology and pathobiology
Rao, S. R., & Fliesler, S. J. (2020) · Journal of Lipid Research · doi:10.1194/jlr.tr120000979 · Cited by 61 · see citing works
Anderson, R. H., Sochacki, K. A., Vuppula, H., Scott, B. L., Bailey, E. M., Schultz, M. M., Kerkvliet, J. G., Taraska, J. W., Hoppe, A. D., & Francis, K. R. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110008 · Cited by 59 · see citing works
Membrane trafficking in the retinal pigment epithelium at a glance
Storm, T., Burgoyne, T., & Futter, C. E. (2020) · Journal of Cell Science · doi:10.1242/jcs.238279 · Cited by 34 · see citing works
Buonfiglio, F., Korb, C. A., Stoffelns, B. M., Pfeiffer, N., & Gericke, A. (2024) · Aging and Disease · doi:10.14336/ad.2024.0124 · Cited by 31 · see citing works
Rao, S. R., & Fliesler, S. J. (2021) · Autophagy · doi:10.1080/15548627.2021.1969634 · Cited by 18 · see citing works
Autophagy in dry AMD: A promising therapeutic strategy for retinal pigment epithelial cell damage
Zhang, Z., Liang, F., Chang, J., Shan, X., Yin, Z., Li, W., & Li, S. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.109889 · Cited by 15 · see citing works
Sharma, A., Kumar, G., & Chattopadhyay, A. (2021) · Traffic : the International Journal of Intracellular Transport · doi:10.1111/tra.12811 · Cited by 13 · see citing works
Cui, X., Kim, H. J., Cheng, C.-H., Jenny, L. A., de Carvalho, J. R. L., Chang, Y.-J., Kong, Y., Hsu, C., Huang, I.-W., Ragi, S. D., et al. (2022) · Human Molecular Genetics · doi:10.1093/hmg/ddac032 · Cited by 13 · see citing works
Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59
Rao, S. R., Fliesler, S. J., Kotla, P., Nguyen, M., & Pittler, S. J. (2020) · Cells · doi:10.3390/cells9040896 · Cited by 13 · see citing works
Kapphahn, R. J., Richards, M. J., Ferrington, D. A., & Fliesler, S. J. (2018) · Experimental Eye Research · doi:10.1016/j.exer.2018.08.006 · Cited by 12 · see citing works
Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis
Chattopadhyay, A., & Sharma, A. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1120373 · Cited by 11 · see citing works
Skelton, L. A., Rao, S. R., Allen, R. S., Motz, C. T., Pardue, M. T., & Fliesler, S. J. (2023) · Experimental Eye Research · doi:10.1016/j.exer.2023.109585 · Cited by 9 · see citing works
Lizama, B. N., Keeling, E., Cho, E.-A., Malagise, E. M., Knezovich, N., Waybright, L., Watto, E., Look, G. C., Caro, V. D., Caggiano, A. O., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-87921-9 · Cited by 8 · see citing works
Pfeffer, B. A., Xu, L., & Fliesler, S. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052339 · Cited by 7 · see citing works
Kolahdouzmohammadi, M., Totonchi, M., & Pahlavan, S. (2020) · Stem Cell Reviews and Reports · doi:10.1007/s12015-020-10077-8 · Cited by 6 · see citing works
Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism?
Piscianz, E., Brumatti, L. V., Tommasini, A., & Marcuzzi, A. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.247441 · Cited by 6 · see citing works
Cholesterol Deficiency Directs Autophagy‐Dependent Secretion of Extracellular Vesicles
Yaeger, J. D. W., Sengupta, S., Walz, A., Morita, M., Morgan, T. K., Vermeer, P. D., & Francis, K. R. (2026) · Journal of Extracellular Vesicles · doi:10.1002/jev2.70218 · Cited by 5 · see citing works
Bottlenecks in the Investigation of Retinal Sterol Homeostasis
Rao, S. R., & Fliesler, S. J. (2024) · Biomolecules · doi:10.3390/biom14030341 · Cited by 4 · see citing works
Adegboro, C. O., Luo, W., Kabra, M., McAdams, R. M., York, N., Wijenayake, R. I., Suchla, K. M., Pillers, D. M., & Pattnaik, B. R. (2024) · Cells · doi:10.3390/cells13201735 · Cited by 2 · see citing works
Scheepers, R., Levi, N. L., & Araujo, R. P. (2024) · Royal Society Open Science · doi:10.1098/rsos.240432 · Cited by 2 · see citing works
Anderson, R. H., Sochacki, K. A., Vuppula, H., Scott, B. L., Bailey, E. M., Schultz, M. M., Kerkvliet, J. G., Taraska, J. W., Hoppe, A. D., & Francis, K. R. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3805160 · Cited by 2 · see citing works
Farkas, M. H., Skelton, L. A., Rao, S. R., Au, E. D., & Fliesler, S. J. (2022) · PubMed Central · Cited by 1 · see citing works
Ma, C., Che, X., Liang, Y., Li, J., Yu, K., Zhao, T., Li, P., & Chen, F. (2025) · Communications Biology · doi:10.1038/s42003-025-08562-2
An In-Gel Fluorescence Technique to Study Autophagy in Human Embryonic Kidney 293 Cells
Rogers, M., Hatton, R. J., Youker, R. T., & Coan, H. (2026) · Advanced Journal of Graduate Research · doi:10.21467/ajgr.17.1.1-10
- Authors
- Ramachandra Rao, S., Pfeffer, B. A., Más Gómez, N., Skelton, L. A., Keiko, U., Sparrow, J. R., Rowsam, A. M., Mitchell, C. H., & Fliesler, S. J.
- Affiliations
- Departments of Ophthalmology (Ross Eye Institute) and Biochemistry, Jacobs School of Medicine and Biomedical Sciences, SUNY-University at Buffalo, Buffalo, NY, USA
- Buffalo VA Medical Center (US)
- Department of Anatomy & Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, USA
- Departments of Ophthalmology (Harkness Eye Institute) and Pathology & Cell Biology, Columbia University, College of Physicians & Surgeons, NY, NY, USA
- Columbia University (US)
- University of Pennsylvania (US)
- Corresponding author
- Fliesler, Steven J.
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2018-07-31
- Volume
- 14
- Issue
- 10
- Pages
- 1796-1817
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC6135634
- OpenAlex
- W2859350743
- Cited by
- 28
- References
- 130
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 6 · 2019: 1 · 2018: 1
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ScholarlyCommons (University of Pennsylvania) (submittedVersion)
- Funders
- NIH (R01 EY007361)
- SJF (1 UL1 TR001412)
- to SUNY-University at Buffalo (R01 EY012951)
- JRS (R01 EY013434)
- CHM
- NEI/NIH (R01 EY007361, R01 EY012951, R01 EY015537)
- Fight for Sight Student Summer Research Grant (None)
- NCATS/NIH (UL1 TR001412)
- RBP Unrestricted Grant (None)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Smith-Lemli-Opitz syndrome, retinal pigment epithelium, phagosome maturation, 7-dehydrocholesterol, cholesterol biosynthesis, AY-9944, rod outer segment phagocytosis, phagosome-lysosome fusion, A2E, bisretinoids, retinal degeneration, lysosomal function
- MeSH terms
- Animals, trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride, Cathepsin D, Cattle, Dehydrocholesterols, Disease Models, Animal, Humans, Lysosomes, Membrane Fusion, Phagocytosis, Phagosomes, Retinoids, Rod Cell Outer Segment, Transcription, Genetic, Protein Biosynthesis, Biomarkers, Cell Culture Techniques, Smith-Lemli-Opitz Syndrome, Rats, Retinal Pigment Epithelium, Ubiquitinated Proteins
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
