Compromised phagosome maturation underlies RPE pathology in cell culture and whole animal models of Smith-Lemli-Opitz Syndrome

References

• Smith DW, Lemli L, Opitz JM. A newly recognized syndrome of multiple congenital anomalies. J Pediatr. 1964 Feb;64:210–217. PubMed PMID: 14119520
   PubMed Web of Science ®Google Scholar
• Bloch K. Sterol structure and function. Steroids. 1989 Mar-May;53(3–5):261–270. PubMed PMID: 2799845
   PubMedGoogle Scholar
• Yu H, Lee MH, Starck L, et al. Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet. 2000 May 22;9(9):1385–1391. PubMed PMID: 10814720
   PubMed Web of Science ®Google Scholar
• Honda A, Tint GS, Salen G, et al. Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opitz syndrome homozygotes. J Lipid Res. 1995 Jul;36(7):1595–1601. PubMed PMID: 7595082
   PubMed Web of Science ®Google Scholar
• Shefer S, Salen G, Batta AK, et al. Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. J Clin Invest. 1995 Oct;96(4):1779–1785. PubMed PMID: 7560069; PubMed Central PMCID: PMC185814.
   PubMed Web of Science ®Google Scholar
• Xu L, Korade Z, Rosado DA Jr. et al. An oxysterol biomarker for 7-dehydrocholesterol oxidation in cell/mouse models for Smith-Lemli-Opitz syndrome. J Lipid Res. 2011 Jun;52(6):1222–1233.. PubMed PMID: 21402677; PubMed Central PMCID: PMC3090243
   PubMed Web of Science ®Google Scholar
• Xu L, Korade Z, Porter NA. Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies. J Am Chem Soc. 2010 Feb 24;132(7):2222–2232.. PubMed PMID: 20121089; PubMed Central PMCID: PMC2839323.
   PubMed Web of Science ®Google Scholar
• Xu L, Sheflin LG, Porter NA, et al. 7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome. Biochim Biophys Acta. 2012 Jun;1821(6):877–883. PubMed PMID: 22425966; PubMed Central PMCID: PMC3340457.
   PubMed Web of Science ®Google Scholar
• Lin AE, Ardinger HH, Ardinger RH Jr., et al. Cardiovascular malformations in Smith-Lemli-Opitz syndrome. Am J Med Genet. 1997 Jan 31;68(3):270–278. PubMed PMID: 9024558
   PubMed Web of Science ®Google Scholar
• Witsch-Baumgartner M, Fitzky BU, Ogorelkova M, et al. Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet. 2000 Feb;66(2):402–412. PubMed PMID: 10677299; PubMed Central PMCID: PMC1288092.
   PubMed Web of Science ®Google Scholar
• Kretzer FL, Hittner HM, Mehta RS. Ocular manifestations of the Smith-Lemli-Opitz syndrome. Arch Ophthalmol. 1981 Nov;99(11):2000–2006. PubMed PMID: 7295150
   PubMedGoogle Scholar
• Garry D, Hansen RM, Moskowitz A, et al. Cone ERG responses in patients with Smith-Lemli-Opitz Syndrome (SLOS). Doc Ophthalmol. 2010 Oct;121(2):85–91. PubMed PMID: 20440536; PubMed Central PMCID: PMC2935499.
   PubMed Web of Science ®Google Scholar
• Fliesler SJ, Peachey NS, Richards MJ, et al. Retinal degeneration in a rodent model of Smith-Lemli-Opitz syndrome: electrophysiologic, biochemical, and morphologic features. Arch Ophthalmol. 2004 Aug;122(8):1190–1200. PubMed PMID: 15302661; PubMed Central PMCID: PMC2865831.
   PubMedGoogle Scholar
• Tu C, Li J, Jiang X, et al. Ion-current-based proteomic profiling of the retina in a rat model of Smith-Lemli-Opitz syndrome. Mol Cell Proteomics. 2013 Dec;12(12):3583–3598. PubMed PMID: 23979708; PubMed Central PMCID: PMC3861709.
   PubMed Web of Science ®Google Scholar
• Boesze-Battaglia K, Damek-Poprawa M, Mitchell DC, et al. Alteration of retinal rod outer segment membrane fluidity in a rat model of Smith-Lemli-Opitz syndrome. J Lipid Res. 2008 Jul;49(7):1488–1499. PubMed PMID: 18344409; PubMed Central PMCID: PMC2431111.
   PubMed Web of Science ®Google Scholar
• Ford DA, Monda JK, Brush RS, et al. Lipidomic analysis of the retina in a rat model of Smith-Lemli-Opitz syndrome: alterations in docosahexaenoic acid content of phospholipid molecular species. J Neurochem. 2008 May;105(3):1032–1047. PubMed PMID: 18182048; PubMed Central PMCID: PMC2721972.
   PubMed Web of Science ®Google Scholar
• Fliesler SJ, Richards MJ, Miller C, et al. Marked alteration of sterol metabolism and composition without compromising retinal development or function. Invest Ophthalmol Vis Sci. 1999 Jul;40(8):1792–1801. PubMed PMID: 10393050
   PubMed Web of Science ®Google Scholar
• Fliesler SJ, Peachey NS, Herron J, et al. Prevention of retinal degeneration in a rat model of Smith-Lemli-Opitz Syndrome. Sci Rep. 2018 Jan 19;8(1):1286. 10.1038/s41598-018-19592-8. PubMed PMID: 29352199; PubMed Central PMCID: PMC5775248
   PubMed Web of Science ®Google Scholar
• Frost LS, Mitchell CH, Boesze-Battaglia K. Autophagy in the eye: implications for ocular cell health. Exp Eye Res. 2014 Jul;124:56–66. PubMed PMID: 24810222; PubMed Central PMCID: PMC4156154.
   PubMed Web of Science ®Google Scholar
• Ferguson TA, Green DR. Autophagy and phagocytosis converge for better vision. Autophagy. 2014 Jan;10(1):165–167.. PubMed PMID: 24220227; PubMed Central PMCID: PMC4028322
   PubMed Web of Science ®Google Scholar
• Young RW, Bok D. Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol. 1969 Aug;42(2):392–403. PubMed PMID: 5792328; PubMed Central PMCID: PMC2107669
   PubMed Web of Science ®Google Scholar
• Kellner U, Kellner S, Weinitz S. Chloroquine retinopathy: lipofuscin- and melanin-related fundus autofluorescence, optical coherence tomography and multifocal electroretinography. Doc Ophthalmol. 2008 Mar;116(2):119–127.. PubMed PMID: 18080820
   PubMed Web of Science ®Google Scholar
• Yoon YH, Cho KS, Hwang JJ, et al. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells. Invest Ophthalmol Vis Sci. 2010 Nov;51(11):6030–6037. PubMed PMID: 20574031.
   PubMed Web of Science ®Google Scholar
• Matsumura M, Ohkuma M, Tsukahara I. Experimental chloroquine retinopathy. Ophthalmic Res. 1986;18(3):172–179. PubMed PMID: 3018650
   PubMed Web of Science ®Google Scholar
• Mahon GJ, Anderson HR, Gardiner TA, et al. Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy. Curr Eye Res. 2004 Apr;28(4):277–284. PubMed PMID: 15259297
   PubMed Web of Science ®Google Scholar
• Kim JY, Zhao H, Martinez J, et al. Noncanonical autophagy promotes the visual cycle. Cell. 2013 Jul 18;154(2):365–376. PubMed PMID: 23870125; PubMed Central PMCID: PMC3744125.
   PubMed Web of Science ®Google Scholar
• Gal A, Li Y, Thompson DA, et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet. 2000 Nov;26(3):270–271. PubMed PMID: 11062461.
   PubMed Web of Science ®Google Scholar
• Francis KR, Ton AN, Xin Y, et al. Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/beta-catenin defects in neuronal cholesterol synthesis phenotypes. Nat Med. 2016 Apr;22(4):388–396. PubMed PMID: 26998835; PubMed Central PMCID: PMC4823163.
   PubMed Web of Science ®Google Scholar
• Maminishkis A, Chen S, Jalickee S, et al. Confluent monolayers of cultured human fetal retinal pigment epithelium exhibit morphology and physiology of native tissue. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3612–3624. PubMed PMID: 16877436; PubMed Central PMCID: PMC1904392.
   PubMed Web of Science ®Google Scholar
• Saari JC, Nawrot M, Kennedy BN, et al. Visual cycle impairment in cellular retinaldehyde binding protein (CRALBP) knockout mice results in delayed dark adaptation. Neuron. 2001 Mar;29(3):739–748. PubMed PMID: 11301032
   PubMed Web of Science ®Google Scholar
• Toops KA, Tan LX, Jiang Z, et al. Cholesterol-mediated activation of acid sphingomyelinase disrupts autophagy in the retinal pigment epithelium. Mol Biol Cell. 2015 Jan 01;26(1):1–14. PubMed PMID: 25378587; PubMed Central PMCID: PMC4279221.
   PubMed Web of Science ®Google Scholar
• Xie R, Nguyen S, McKeehan WL, et al. Acetylated microtubules are required for fusion of autophagosomes with lysosomes. BMC Cell Biol. 2010 Nov 22;11:89.. PubMed PMID: 21092184; PubMed Central PMCID: PMC2995476.
   PubMed Web of Science ®Google Scholar
• Marmorstein AD, Marmorstein LY, Rayborn M, et al. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12758–12763. PubMed PMID: 11050159; PubMed Central PMCID: PMC18837.
   PubMed Web of Science ®Google Scholar
• Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001 Dec;25(4):402–408.. PubMed PMID: 11846609
   PubMed Web of Science ®Google Scholar
• Pfeffer BA, Becerra SP, Borst DE, et al. Expression of transthyretin and retinol binding protein mRNAs and secretion of transthyretin by cultured monkey retinal pigment epithelium. Mol Vis. 2004 Jan;14(10):23–30. PubMed PMID: 14737066
   Google Scholar
• Pfeffer BA. Improved methodology for cell culture of human and monkey retinal pigment epithelium. Prog Retin Res. 1991;10:251–291.. PubMed PMID: WOS:A1991HK14200009; English
   Google Scholar
• Yu H, Tint GS, Salen G, et al. Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-G–>C is found in over sixty percent of US propositi. Am J Med Genet. 2000 Feb 14;90(4):347–350. PubMed PMID: 10710236
   PubMed Web of Science ®Google Scholar
• Krakowiak PA, Nwokoro NA, Wassif CA, et al. Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am J Med Genet. 2000 Sep 18;94(3):214–227. PubMed PMID: 10995508
   PubMed Web of Science ®Google Scholar
• Bjorkoy G, Lamark T, Brech A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005 Nov 21;171(4):603–614. PubMed PMID: 16286508; PubMed Central PMCID: PMC2171557.
   PubMed Web of Science ®Google Scholar
• Wang L, Cano M, Handa JT. p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium. Biochim Biophys Acta. 2014 Jul;1843(7):1248–1258.. PubMed PMID: 24667411; PubMed Central PMCID: PMC4019388
   PubMed Web of Science ®Google Scholar
• Miettinen TP, Bjorklund M. Mevalonate pathway regulates cell size homeostasis and proteostasis through autophagy. Cell Rep. 2015 Dec 22;13(11):2610–2620.. PubMed PMID: 26686643; PubMed Central PMCID: PMC4709259.
   PubMed Web of Science ®Google Scholar
• Tricarico PM, Crovella S, Celsi F. Mevalonate pathway blockade, mitochondrial dysfunction and autophagy: a possible link. Int J Mol Sci. 2015 Jul 15;16(7):16067–16084.. PubMed PMID: 26184189; PubMed Central PMCID: PMC4519939.
   PubMed Web of Science ®Google Scholar
• Coffey EE, Beckel JM, Laties AM, et al. Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience. 2014 Mar 28;263:111–124.. PubMed PMID: 24418614; PubMed Central PMCID: PMC4028113.
   PubMed Web of Science ®Google Scholar
• Guha S, Coffey EE, Lu W, et al. Approaches for detecting lysosomal alkalinization and impaired degradation in fresh and cultured RPE cells: evidence for a role in retinal degenerations. Exp Eye Res. 2014 Sep;126:68–76. PubMed PMID: 25152362; PubMed Central PMCID: PMC4143779.
   PubMed Web of Science ®Google Scholar
• Barth S, Glick D, Macleod KF. Autophagy: assays and artifacts. J Pathol. 2010 Jun;221(2):117–124.. PubMed PMID: 20225337; PubMed Central PMCID: PMC2989884
   PubMed Web of Science ®Google Scholar
• Tanida I, Ueno T, Kominami E. LC3 and Autophagy. Methods Mol Biol. 2008;445:77–88.. PubMed PMID: 18425443
   PubMedGoogle Scholar
• Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007 Aug 17;282(33):24131–24145. PubMed PMID: 17580304.
   PubMed Web of Science ®Google Scholar
• Gottlieb RA, Andres AM, Sin J, et al. Untangling autophagy measurements: all fluxed up. Circ Res. 2015 Jan 30;116(3):504–514.. PubMed PMID: 25634973; PubMed Central PMCID: PMC4313387.
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1–222.. PubMed PMID: 26799652; PubMed Central PMCID: PMC4835977
   PubMed Web of Science ®Google Scholar
• Sahani MH, Itakura E, Mizushima N. Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids. Autophagy. 2014 Mar;10(3):431–441.. PubMed PMID: 24394643; PubMed Central PMCID: PMC4077882
   PubMed Web of Science ®Google Scholar
• Hanada T, Noda NN, Satomi Y, et al. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem. 2007 Dec 28;282(52):37298–37302. PubMed PMID: 17986448.
   PubMed Web of Science ®Google Scholar
• Kim M, Sandford E, Gatica D, et al. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. Elife. 2016 Jan;26:5. PubMed PMID: 26812546; PubMed Central PMCID: PMC4786408.
   Google Scholar
• Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010 Feb 5;140(3):313–326.. PubMed PMID: 20144757; PubMed Central PMCID: PMC2852113.
   PubMed Web of Science ®Google Scholar
• Deguchi J, Yamamoto A, Yoshimori T, et al. Acidification of phagosomes and degradation of rod outer segments in rat retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1994 Feb;35(2):568–579. PubMed PMID: 8113008
   PubMed Web of Science ®Google Scholar
• Bosch E, Horwitz J, Bok D. Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction. J Histochem Cytochem. 1993 Feb;41(2):253–263.. PubMed PMID: 8419462
   PubMed Web of Science ®Google Scholar
• Wavre-Shapton ST, Meschede IP, Seabra MC, et al. Phagosome maturation during endosome interaction revealed by partial rhodopsin processing in retinal pigment epithelium. J Cell Sci. 2014 Sep 01;127(Pt 17):3852–3861. PubMed PMID: 25074813; PubMed Central PMCID: PMC4150067.
   PubMed Web of Science ®Google Scholar
• Esteve-Rudd J, Lopes VS, Jiang M, et al. In vivo and in vitro monitoring of phagosome maturation in retinal pigment epithelium cells. Adv Exp Med Biol. 2014;801:85–90.. PubMed PMID: 24664684
   PubMed Web of Science ®Google Scholar
• Seglen PO, Gordon PB. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1889–1892. PubMed PMID: 6952238; PubMed Central PMCID: PMC346086
   PubMed Web of Science ®Google Scholar
• Fliesler SJ. Antioxidants: the missing key to improved therapeutic intervention in Smith-Lemli-Opitz Syndrome? Hereditary Genet. 2013 Dec 1;2(2):119.. PubMed PMID: 24533230; PubMed Central PMCID: PMC3925008.
   PubMedGoogle Scholar
• Fliesler SJ. Retinal degeneration and cholesterol deficiency [Book Chaper]. Handbook Nutrition, Diet Eye. 2014;1:287–297.
   Google Scholar
• Liu J, Itagaki Y, Ben-Shabat S, et al. The biosynthesis of A2E, a fluorophore of aging retina, involves the formation of the precursor, A2-PE, in the photoreceptor outer segment membrane. J Biol Chem. 2000 Sep 22;275(38):29354–29360. PubMed PMID: 10887199.
   PubMed Web of Science ®Google Scholar
• Sparrow JR, Boulton M. RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res. 2005 May;80(5):595–606.. PubMed PMID: 15862166
   PubMed Web of Science ®Google Scholar
• Crouch RK, Koutalos Y, Kono M, et al. A2E and Lipofuscin. Prog Mol Biol Transl Sci. 2015;134:449–463.. PubMed PMID: 26310170
   PubMed Web of Science ®Google Scholar
• LaVail MM. Outer segment disc shedding and phagocytosis in the outer retina. Trans Ophthalmol Soc U K. 1983;103(Pt 4):397–404. PubMed PMID: 6380008
   PubMedGoogle Scholar
• Correa-Cerro LS, Wassif CA, Kratz L, et al. Development and characterization of a hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy. Hum Mol Genet. 2006 Mar 15;15;(6):839–851. PubMed PMID: 16446309. DOI:10.1093/hmg/ddl003.
   PubMed Web of Science ®Google Scholar
• Marcos J, Shackleton CH, Buddhikot MM, et al. Cholesterol biosynthesis from birth to adulthood in a mouse model for 7-dehydrosterol reductase deficiency (Smith-Lemli-Opitz syndrome). Steroids. 2007 Oct;72(11–12):802–808. PubMed PMID: 17714750; PubMed Central PMCID: PMC2911235.
   PubMed Web of Science ®Google Scholar
• Caldwell RB, McLaughlin BJ. Freeze-fracture study of filipin binding in photoreceptor outer segments and pigment epithelium of dystrophic and normal retinas. J Comp Neurol. 1985 Jun 22;236(4):523–537.. PubMed PMID: 4056101.
   PubMed Web of Science ®Google Scholar
• Punnonen EL, Pihakaski K, Mattila K, et al. Intramembrane particles and filipin labelling on the membranes of autophagic vacuoles and lysosomes in mouse liver. Cell Tissue Res. 1989 Nov;258(2):269–276. PubMed PMID: 2582478
   PubMed Web of Science ®Google Scholar
• Brandstaetter H, Kishi-Itakura C, Tumbarello DA, et al. Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion. Autophagy. 2014;10(12):2310–2323.. PubMed PMID: 25551774; PubMed Central PMCID: PMC4502697
   PubMed Web of Science ®Google Scholar
• Amer AO, Byrne BG, Swanson MS. Macrophages rapidly transfer pathogens from lipid raft vacuoles to autophagosomes. Autophagy. 2005 Apr;1(1):53–58. PubMed PMID: 16874021; PubMed Central PMCID: PMC1584280
   PubMed Web of Science ®Google Scholar
• Koga H, Kaushik S, Cuervo AM. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 2010 Aug;24(8):3052–3065.. PubMed PMID: 20375270; PubMed Central PMCID: PMC2909278
   PubMed Web of Science ®Google Scholar
• Rai A, Pathak D, Thakur S, et al. Dynein clusters into lipid microdomains on phagosomes to drive rapid transport toward lysosomes. Cell. 2016 Feb 11;164(4):722–734. PubMed PMID: 26853472; PubMed Central PMCID: PMC4752818.
   PubMed Web of Science ®Google Scholar
• Wijdeven RH, Janssen H, Nahidiazar L, et al. Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway. Nat Commun. 2016 Jun 10;7:11808.. PubMed PMID: 27283760; PubMed Central PMCID: PMC4906411.
   PubMed Web of Science ®Google Scholar
• Chang S, Ren G, Steiner RD, et al. Elevated autophagy and mitochondrial dysfunction in the Smith-Lemli-Opitz Syndrome. Mol Genet Metab Rep. 2014;1:431–442.. PubMed PMID: 25405082; PubMed Central PMCID: PMC4231544
   PubMedGoogle Scholar
• Fong JT, Kells RM, Gumpert AM, et al. Internalized gap junctions are degraded by autophagy. Autophagy. 2012 May 01;8(5):794–811. PubMed PMID: 22635056; PubMed Central PMCID: PMC3378421.
   PubMed Web of Science ®Google Scholar
• Carette D, Gilleron J, Denizot JP, et al. New cellular mechanisms of gap junction degradation and recycling. Biol Cell. 2015 Jul;107(7):218–231. PubMed PMID: 25818265.
   PubMed Web of Science ®Google Scholar
• Ma JH, Wang JJ, Li J, et al. The role of IRE-XBP1 pathway in regulation of retinal pigment epithelium tight junctions. Invest Ophthalmol Vis Sci. 2016 Oct 1;57(13):5244–5252. PubMed PMID: 27701635; PubMed Central PMCID: PMC5054729.
   PubMed Web of Science ®Google Scholar
• Gordiyenko N, Campos M, Lee JW, et al. RPE cells internalize low-density lipoprotein (LDL) and oxidized LDL (oxLDL) in large quantities in vitro and in vivo. Invest Ophthalmol Vis Sci. 2004 Aug;45(8):2822–2829. PubMed PMID: 15277509.
   PubMed Web of Science ®Google Scholar
• Tserentsoodol N, Sztein J, Campos M, et al. Uptake of cholesterol by the retina occurs primarily via a low density lipoprotein receptor-mediated process. Mol Vis. 2006 Oct;27(12):1306–1318. PubMed PMID: 17110914
   Google Scholar
• Claudepierre T, Paques M, Simonutti M, et al. Lack of Niemann-Pick type C1 induces age-related degeneration in the mouse retina. Mol Cell Neurosci. 2010 Jan;43(1):164–176. PubMed PMID: 19883762.
   PubMed Web of Science ®Google Scholar
• Levin R, Grinstein S, Canton J. The life cycle of phagosomes: formation, maturation, and resolution. Immunol Rev. 2016 Sep;273(1):156–179.. PubMed PMID: 27558334
   PubMed Web of Science ®Google Scholar
• Feng Y, He D, Yao Z, et al. The machinery of macroautophagy. Cell Res. 2014 Jan;24(1):24–41. PubMed PMID: 24366339; PubMed Central PMCID: PMC3879710.
   PubMed Web of Science ®Google Scholar
• Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 2010 Jul;13(7):805–811.. PubMed PMID: 20581817; PubMed Central PMCID: PMC4038747
   PubMed Web of Science ®Google Scholar
• Sinha D, Valapala M, Shang P, et al. Lysosomes: regulators of autophagy in the retinal pigmented epithelium. Exp Eye Res. 2016 Mar;144:46–53. PubMed PMID: 26321509; PubMed Central PMCID: PMC4698066.
   PubMed Web of Science ®Google Scholar
• Ferrington DA, Sinha D, Kaarniranta K. Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration. Prog Retin Eye Res. 2016 Mar;51:69–89. PubMed PMID: 26344735; PubMed Central PMCID: PMC4769684.
   PubMed Web of Science ®Google Scholar
• Lavandero S, Chiong M, Rothermel BA, et al. Autophagy in cardiovascular biology. J Clin Invest. 2015 Jan;125(1):55–64. PubMed PMID: 25654551; PubMed Central PMCID: PMC4382263.
   PubMed Web of Science ®Google Scholar
• Vieira OV, Botelho RJ, Grinstein S. Phagosome maturation: aging gracefully. Biochem J. 2002 Sep 15;366(Pt 3):689–704.. PubMed PMID: 12061891; PubMed Central PMCID: PMC1222826.
   PubMed Web of Science ®Google Scholar
• Terman A, Kurz T, Navratil M, et al. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal. 2010 Apr;12(4):503–535. PubMed PMID: 19650712; PubMed Central PMCID: PMC2861545.
   PubMed Web of Science ®Google Scholar
• Cuervo AM, Wong E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 2014 Jan;24(1):92–104.. PubMed PMID: 24281265; PubMed Central PMCID: PMC3879702
   PubMed Web of Science ®Google Scholar
• Mitter SK, Song C, Qi X, et al. Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy. 2014;10(11):1989–2005.. PubMed PMID: 25484094; PubMed Central PMCID: PMC4502658
   PubMed Web of Science ®Google Scholar
• Sparrow JR, Yamamoto K. The bisretinoids of RPE lipofuscin: a complex mixture. Adv Exp Med Biol. 2012;723:761–767.. PubMed PMID: 22183404
   PubMed Web of Science ®Google Scholar
• Ng KP, Gugiu B, Renganathan K, et al. Retinal pigment epithelium lipofuscin proteomics. Mol Cell Proteomics. 2008 Jul;7(7):1397–1405. PubMed PMID: 18436525; PubMed Central PMCID: PMC2493379.
   PubMed Web of Science ®Google Scholar
• Lakkaraju A, Finnemann SC, Rodriguez-Boulan E. The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11026–11031.. PubMed PMID: 17578916; PubMed Central PMCID: PMC1904145.
   PubMed Web of Science ®Google Scholar
• Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013 Aug;19(8):983–997.. PubMed PMID: 23921753
   PubMed Web of Science ®Google Scholar
• Saadat KA, Murakami Y, Tan X, et al. Inhibition of autophagy induces retinal pigment epithelial cell damage by the lipofuscin fluorophore A2E. FEBS Open Bio. 2014;4:1007–1014.. PubMed PMID: 25473597; PubMed Central PMCID: PMC4250541
   PubMed Web of Science ®Google Scholar
• Lei L, Tzekov R, Li H, et al. Inhibition or stimulation of autophagy affects early formation of lipofuscin-like autofluorescence in the retinal pigment epithelium cell. Int J Mol Sci. 2017 Mar 29;18(4). PubMed PMID: 28353645; PubMed Central PMCID: PMC5412314. DOI:10.3390/ijms18040728.
   Web of Science ®Google Scholar
• Simons K, Ehehalt R. Cholesterol, lipid rafts, and disease. J Clin Invest. 2002 Sep;110(5):597–603.. PubMed PMID: 12208858; PubMed Central PMCID: PMC151114
   PubMed Web of Science ®Google Scholar
• Mayor S, Rao M. Rafts: scale-dependent, active lipid organization at the cell surface. Traffic. 2004 Apr;5(4):231–240.. PubMed PMID: 15030564
   PubMed Web of Science ®Google Scholar
• Sarkar S, Carroll B, Buganim Y, et al. Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease. Cell Rep. 2013 Dec 12;5(5):1302–1315. PubMed PMID: 24290752; PubMed Central PMCID: PMC3957429.
   PubMed Web of Science ®Google Scholar
• Ishibashi S, Yamazaki T, Okamoto K. Association of autophagy with cholesterol-accumulated compartments in Niemann-Pick disease type C cells. J Clin Neurosci. 2009 Jul;16(7):954–959.. PubMed PMID: 19342246
   PubMed Web of Science ®Google Scholar
• Huynh KK, Gershenzon E, Grinstein S. Cholesterol accumulation by macrophages impairs phagosome maturation. J Biol Chem. 2008 Dec 19;283(51):35745–35755.. PubMed PMID: 18955491.
   PubMed Web of Science ®Google Scholar
• Rocha N, Kuijl C, van der Kant R, et al. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning. J Cell Biol. 2009 Jun 29;185(7):1209–1225. PubMed PMID: 19564404; PubMed Central PMCID: PMC2712958.
   PubMed Web of Science ®Google Scholar
• Hoppe G, O’Neil J, Hoff HF, et al. Accumulation of oxidized lipid-protein complexes alters phagosome maturation in retinal pigment epithelium. Cell Mol Life Sci. 2004 Jul;61(13):1664–1674. PubMed PMID: 15224189.
   PubMed Web of Science ®Google Scholar
• Frost LS, Lopes VS, Bragin A, et al. The contribution of melanoregulin to microtubule-associated protein 1 light chain 3 (LC3) associated phagocytosis in retinal pigment epithelium. Mol Neurobiol. 2015 Dec;52(3):1135–1151. 10.1007/s12035-014-8920-5. PubMed PMID: 25301234
   PubMed Web of Science ®Google Scholar
• Xu L, Korade Z, Rosado DA Jr. et al. Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells. J Lipid Res. 2013 Apr;54(4):1135–1143.. PubMed PMID: 23381570; PubMed Central PMCID: PMC3605989
   PubMed Web of Science ®Google Scholar
• Xu L, Liu W, Sheflin LG, et al. Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome. J Lipid Res. 2011 Oct;52(10):1810–1820. PubMed PMID: 21817059; PubMed Central PMCID: PMC3173002.
   PubMed Web of Science ®Google Scholar
• Wassif CA, Vied D, Tsokos M, et al. Cholesterol storage defect in RSH/Smith-Lemli-Opitz syndrome fibroblasts. Mol Genet Metab. 2002 Apr;75(4):325–334. PubMed PMID: 12051964.
   PubMed Web of Science ®Google Scholar
• Elrick MJ, Yu T, Chung C, et al. Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease. Hum Mol Genet. 2012 Nov 15;21(22):4876–4887. PubMed PMID: 22872701; PubMed Central PMCID: PMC3607480.
   PubMed Web of Science ®Google Scholar
• Cox BE, Griffin EE, Ullery JC, et al. Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification. J Lipid Res. 2007 May;48(5):1012–1021. PubMed PMID: 17308299.
   PubMed Web of Science ®Google Scholar
• Ying L, Matabosch X, Serra M, et al. Biochemical and physiological improvement in a mouse model of Smith-Lemli-Opitz Syndrome (SLOS) following gene transfer with AAV vectors. Mol Genet Metab Rep. 2014;1:103–113.. PubMed PMID: 25024934; PubMed Central PMCID: PMC4093838
   PubMedGoogle Scholar
• Muniz-Feliciano L, Doggett TA, Zhou Z, et al. RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye. Autophagy. 2017;13(12):2072–2085.. PubMed PMID: 28933590; PubMed Central PMCID: PMC5788552
   PubMed Web of Science ®Google Scholar
• Ferrer M, Corneo B, Davis J, et al. A multiplex high-throughput gene expression assay to simultaneously detect disease and functional markers in induced pluripotent stem cell-derived retinal pigment epithelium. Stem Cells Transl Med. 2014 Aug;3(8):911–922. PubMed PMID: 24873859; PubMed Central PMCID: PMC4116245.
   PubMed Web of Science ®Google Scholar
• Miyagishima KJ, Wan Q, Corneo B, et al. In pursuit of authenticity: induced pluripotent stem cell-derived retinal pigment epithelium for clinical applications. Stem Cells Transl Med. 2016 Nov;5(11):1562–1574. PubMed PMID: 27400791; PubMed Central PMCID: PMC5070511.
   PubMed Web of Science ®Google Scholar
• Saini JS, Corneo B, Miller JD, et al. Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell. 2017 May 4;20(5):635–647 e7. PubMed PMID: 28132833; PubMed Central PMCID: PMC5419856.
   PubMed Web of Science ®Google Scholar
• Pfeffer BA, Xu L, Porter NA, et al. Differential cytotoxic effects of 7-dehydrocholesterol-derived oxysterols on cultured retina-derived cells: dependence on sterol structure, cell type, and density. Exp Eye Res. 2016 Apr;145:297–316. PubMed PMID: 26854824; PubMed Central PMCID: PMC5024725.
   PubMed Web of Science ®Google Scholar
• Cham BE, Knowles BR. A solvent system for delipidation of plasma or serum without protein precipitation. J Lipid Res. 1976 Mar;17(2):176–181. PubMed PMID: 818332
   PubMed Web of Science ®Google Scholar
• Keller RK, Mitchell DA, Goulah CC, et al. Hepatic isoprenoid metabolism in a rat model of Smith-Lemli-Opitz Syndrome. Lipids. 2013 Mar;48(3):219–229. PubMed PMID: 23361583; PubMed Central PMCID: PMC3595616.
   PubMed Web of Science ®Google Scholar
• Wassif CA, Krakowiak PA, Wright BS, et al. Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts. Mol Genet Metab. 2005 Jun;85(2):96–107. PubMed PMID: 15896653.
   PubMed Web of Science ®Google Scholar
• Sievers F, Wilm A, Dineen D, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011 Oct 11;7:539.. PubMed PMID: 21988835; PubMed Central PMCID: PMC3261699.
   PubMed Web of Science ®Google Scholar
• Marmorstein AD, Marmorstein LY, Sakaguchi H, et al. Spectral profiling of autofluorescence associated with lipofuscin, Bruch’s Membrane, and sub-RPE deposits in normal and AMD eyes. Invest Ophthalmol Vis Sci. 2002 Jul;43(7):2435–2441. PubMed PMID: 12091448
   PubMed Web of Science ®Google Scholar
• Yamamoto K, Yoon KD, Ueda K, et al. A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine. Invest Ophthalmol Vis Sci. 2011 Nov 25;52(12):9084–9090. PubMed PMID: 22039245; PubMed Central PMCID: PMC3231846.
   PubMed Web of Science ®Google Scholar
• Baltazar GC, Guha S, Lu W, et al. Acidic nanoparticles are trafficked to lysosomes and restore an acidic lysosomal pH and degradative function to compromised ARPE-19 cells. PLoS One. 2012;7(12):e49635.. PubMed PMID: 23272048; PubMed Central PMCID: PMC3525582
   PubMed Web of Science ®Google Scholar
• Brandl C, Zimmermann SJ, Milenkovic VM, et al. In-depth characterisation of retinal pigment epithelium (RPE) cells derived from human induced pluripotent stem cells (hiPSC). Neuromolecular Med. 2014 Sep;16(3):551–564. PubMed PMID: 24801942; PubMed Central PMCID: PMC4119585.
   PubMed Web of Science ®Google Scholar