Skip to main content

Advertisement

Log in

The Contribution of Melanoregulin to Microtubule-Associated Protein 1 Light Chain 3 (LC3) Associated Phagocytosis in Retinal Pigment Epithelium

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

A main requisite in the phagocytosis of ingested material is a coordinated series of maturation steps which lead to the degradation of ingested cargo. Photoreceptor outer segment (POS) renewal involves phagocytosis of the distal disk membranes by the retinal pigment epithelium (RPE). Previously, we identified melanoregulin (MREG) as an intracellular cargo-sorting protein required for the degradation of POS disks. Here, we provide evidence that MREG-dependent processing links both autophagic and phagocytic processes in LC3-associated phagocytosis (LAP). Ingested POS phagosomes are associated with endogenous LC3 and MREG. The LC3 association with POSs exhibited properties of LAP; it was independent of rapamycin pretreatment, but dependent on Atg5. Loss of MREG resulted in a decrease in the extent of LC3-POS association. Studies using DQ™-BSA suggest that loss of MREG does not compromise the association and fusion of LC3-positive phagosomes with lysosomes. Furthermore, the mechanism of MREG action is likely through a protein complex that includes LC3, as determined by colocalization and immunoprecipitation in both RPE cells and macrophages. We posit that MREG participates in coordinating the association of phagosomes with LC3 for content degradation with the loss of MREG leading to phagosome accumulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

POS:

Photoreceptor outer segment

RPE:

Retinal pigment epithelium

TR:

Texas red

LC3:

Microtubule-associated protein 1 light chain 3

IP:

Immunoprecipitation

MREG:

Melanoregulin

IEM:

Immuno-electron microscopy

References

  1. Oczypok EA, Oury TD, Chu CT (2013) It’s a cell-eat-cell world: Autophagy and phagocytosis. Am J Pathol 182:612–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Codogno P, Mehrpour M, Proikas-Cezanne T (2011) Canonical and noncanonical autophagy: Variations on a common theme of self-eating? Nat Rev Mol Cell 13:7–12

    Article  Google Scholar 

  3. Kon M, Cuervo AM (2010) Chaperone-mediated autophagy in health and disease. FEBS Lett 584:1399–1404

    Article  CAS  PubMed  Google Scholar 

  4. Martinez J, Almendinger J, Oberst A, Ness R, Dillon CP, Fitzgerald P, Hengartner MO, Green DR (2011) Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc Natl Acad Sci U S A 108:17396–17401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Florey O, Kim SE, Sandoval CP, Haynes CM, Overholtzer M (2011) Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat Cell Biol 13:1335–1343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Florey O, Overholtzer M (2012) Autophagy proteins in macroendocytic engulfment. Trends Cell Biol 22:374–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sanjuan MA, Milasta S, Green DR (2009) Toll-like receptor signaling in the lysosomal pathways. Immunol Rev 227:203–220

    Article  CAS  PubMed  Google Scholar 

  8. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–1257

    Article  CAS  PubMed  Google Scholar 

  9. Young RW, Droz B (1968) The renewal of protein in retinal rods and cones. J Cell Biol 39:169–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim JY, Zhao H, Martinez J, Doggett TA, Kolesnikov AV, Tang PH, Ablonczy Z, Chan CC, Zhou Z, Green DR, Ferguson TA (2013) Noncanonical autophagy promotes the visual cycle. Cell 154:365–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Young RW (1967) The renewal of photoreceptor cell outer segments. J Cell Biol 33:61–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Young RW, Bok D (1969) Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42:392–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kevany BM, Palczewski K (2010) Phagocytosis of retinal rod and cone photoreceptors. Physiology 25:8–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881

    Article  CAS  PubMed  Google Scholar 

  15. Beatty S, Kohl M, Phil M, Henson D, Boulton M (2000) Surv Ophthalmol 45:115–134

    Article  CAS  PubMed  Google Scholar 

  16. Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14:194–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kopitz J, Holz FG, Kaemmerer E, Schutt F (2004) Lipids and lipid peroxidation products in the pathogenesis of age-related macular degeneration. Biochimie 86:825–831

    Article  CAS  PubMed  Google Scholar 

  18. Chen PM, Gombart ZJ, Chen JW (2011) Chloroquine treatment of ARPE-19 cells leads to lysosome dilation and intracellular lipid accumulation: Possible implications of lysosomal dysfunction in macular degeneration. Cell Biosci 1:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kaaraniranta K, Salminen A, Eskelinem EL, and Kopitz J (2009) Heat shock proteins as gatekeepers of proteolytic pathwyas-implications for age-related macular degeneration. Ageing Res Rev, 1280139

  20. Terman A, Gustafsson B, Brunk UT (2007) Autophagy, Organelles and ageing. J Pathol 211:134–143

    Article  CAS  PubMed  Google Scholar 

  21. Reme C, Wirz-Justice A, Rhyner A, Hofmann S (1986) Circadian rhythm in the light response of rat retinal disk-shedding and autophagy. Brain Res 369:356–360

    Article  CAS  PubMed  Google Scholar 

  22. Reme CE, Wolfrum U, Imsand C, Hafezi F, Williams TP (1999) Photoreceptor autophagy: Effects of light history on number and opsin content of degradative vacuoles. Invest Ophthalmol Vis Sci 40:2398–2404

    CAS  PubMed  Google Scholar 

  23. Frost LS, Mitchell CH, Boesze-Battaglia K (2014) Autophagy in the eye: Implications for ocular cell health. Exp Eye Res 124c:56–66

    Article  Google Scholar 

  24. Kunchithapautham K, Rohrer B (2007) Autophagy is one of the multiple mechanisms active in photoreceptor degeneration. Autophagy 3:65–66

    Article  CAS  PubMed  Google Scholar 

  25. Kunchithapautham K, Rohrer B (2007) Apoptosis and autophagy in photoreceptors exposed to oxidative stress. Autophagy 3:433–441

    Article  CAS  PubMed  Google Scholar 

  26. Reme C (1981) Autophagy in rods and cones of the vertebrate retina. Dev Ophthalmol 4:101–148

    Article  CAS  PubMed  Google Scholar 

  27. Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH (2009) Autophagy and exosomes in the aged retinal pigment epithelium: Possible relevance to drusen formation and age-related macular degeneration. PLoS One 4:e4160

    Article  PubMed  PubMed Central  Google Scholar 

  28. Chen Y, Sawada O, Kohno H, Le YZ, Subauste C, Maeda T, Maeda A (2013) Autophagy protects the retina from light-induced degeneration. J Biol Chem 288:7506–7518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yao J, Jia L, Shelby SJ, Ganios AM, Feathers K, Thompson DA, Zacks DN (2014) Circadian and non-circadian modulation of autophagy in photoreceptors and retinal pigment epithelium. Invest Ophthalmol Vis Sci 55:3237–3246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. O’Sullivan TN, Wu XS, Rachel RA, Huang JD, Swing DA, Matesic LE, Hammer JA 3rd, Copeland NG, Jenkins NA (2004) dsu functions in a MYO5A-independent pathway to suppress the coat color of dilute mice. Proc Natl Acad Sci U S A 101:16831–16836

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wu XS, Masedunskas A, Weigert R, Copeland NG, Jenkins NA, and Hammer JA (2012) Melanoregulin regulates a shedding mechanism that drives melanosome transfer from melanocytes to keratinocytes. Proceedings of the National Academy of Sciences of the United States of America

  32. Rachel RA, Nagashima K, O’Sullivan TN, Frost LS, Stefano FP, Marigo V, Boesze-Battaglia K (2012) Melanoregulin, product of the dsu locus, links the BLOC-pathway and OA1 in organelle biogenesis. PLoS One 7:e42446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Damek-Poprawa M, Diemer T, Lopes VS, Lillo C, Harper DC, Marks MS, Wu Y, Sparrow JR, Rachel RA, Williams DS, Boesze-Battaglia K (2009) Melanoregulin (MREG) modulates lysosome function in pigment epithelial cells. J Biol Chem 284:10877–10889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Frost LS, Lopes VS, Stefano FP, Bragin A, Williams DS, Mitchell CH, Boesze-Battaglia K (2013) Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium. Vis Neurosci 30:55–64

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gibbs D, Kitamoto J, Williams DS (2003) Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proc Natl Acad Sci U S A 100:6481–6486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. LaVail MM (1980) Circadian nature of rod outer segment disc shedding in the rat. Invest Ophthalmol Vis Sci 19:407

    CAS  PubMed  Google Scholar 

  37. Mao Y, Finnemann SC (2012) Essential diurnal Rac1 activation during retinal phagocytosis requires αvβ5 integrin but not tyrosine kinases focal adhesion kinase or Mer tyrosine kinase. Mol Biol Cell 23:1104–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Boesze-Battaglia K, Song H, Sokolov M, Lillo C, Pankoski-Walker L, Gretzula C, Gallagher B, Rachel RA, Jenkins NA, Copeland NG, Morris F, Jacob J, Yeagle P, Williams DS, Damek-Poprawa M (2007) The tetraspanin protein peripherin-2 forms a complex with melanoregulin, a putative membrane fusion regulator. Biochemistry 46:1256–1272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Deguchi J, Yamamoto A, Yoshimori T, Sugasawa K, Moriyama Y, Futai M, Suzuki T, Kato K, Uyama M, Tashiro Y (1994) Acidification of phagosomes and degradation of rod outer segments in rat retinal pigment epithelium. Invest Ophthalmol Vis Sci 35:568–579

    CAS  PubMed  Google Scholar 

  40. Woessner JF Jr (1977) Specificity and biological role of cathepsin D. Adv Exp Med Biol 95:313–327

    Article  PubMed  Google Scholar 

  41. Bosch E, Horwitz J, Bok D (1993) Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction. J Histochem Cytochem 41:253

    Article  CAS  PubMed  Google Scholar 

  42. Reme CA, Sulser M (1977) Diurnal variation of autophagy in rod visual cells in the rat. Graefes Archiv Opthalmologie 203:261–270

    Article  CAS  Google Scholar 

  43. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Torisu T, Torisu K, Lee IH, Liu J, Malide D, Combs CA, Wu XS, Rovira II, Fergusson MM, Weigert R, Connelly PS, Daniels MP, Komatsu M, Cao L, Finkel T (2013) Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor. Nat Med 19:1281–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tanida I, Sou YS, Ezaki J, Minematsu-Ikeguchi N, Ueno T, Kominami E (2004) HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-associated protein light chain 3- and GABAA receptor-associated protein-phospholipid conjugates. J Biol Chem 279:36268–36276

    Article  CAS  PubMed  Google Scholar 

  46. Cuervo AM (2004) Autophagy: in sickness and in health. Trends Cell Biol 14:70–77

    Article  PubMed  Google Scholar 

  47. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Massey AC, Zhang C, Cuervo AM (2006) Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 73:205–235

    Article  CAS  PubMed  Google Scholar 

  49. Krohne TU, Stratmann NK, Kopitz J, Holz FG (2010) Effects of lipid peroxidation products on lipofuscinogenesis and autophagy in human retinal pigment epithelial cells. Exp Eye Res 90:465–471

    Article  CAS  PubMed  Google Scholar 

  50. Birgisdottir AB, Lamark T, Johansen T (2013) The LIR motif—Crucial for selective autophagy. J Cell Sci 126:3237–3247

    CAS  PubMed  Google Scholar 

  51. Dorn BR, Dunn WA Jr, Progulske-Fox A (2002) Bacterial interactions with the autophagic pathway. Cell Microbiol 4:1–10

    Article  CAS  PubMed  Google Scholar 

  52. Maminishkis A, Chen S, Jalickee S, Banzon T, Shi G, Wang FE, Ehalt T, Hammer JA, Miller SS (2006) Confluent monolayers of cultured human fetal retinal pigment epithelium exhibit morphology and physiology of native tissue. Invest Ophthalmol Vis Sci 47:3612–3624

    Article  PubMed  PubMed Central  Google Scholar 

  53. Dunn KC, Aotaki-Keen AE, Putkey FR, Hjelmeland LM (1996) ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp Eye Res 62:155–169

    Article  CAS  PubMed  Google Scholar 

  54. Boesze-Battaglia K, Albert AD (1992) Phospholipid distribution among bovine rod outer segment plasma membrane and disk membranes. Exp Eye Res 54:821–823

    Article  CAS  PubMed  Google Scholar 

  55. Vazquez CL, Colombo MI (2009) Assays to assess autophagy induction and fusion of autophagic vacuoles with a degradative compartment, using monodansylcadaverine (MDC) and DQ-BSA. Methods Enzymol 452:85–95

    Article  CAS  PubMed  Google Scholar 

  56. Lopes VS, Gibbs D, Libby RT, Aleman TS, Welch DL, Lillo C, Jacobson SG, Radu RA, Steel KP, Williams DS (2011) The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65. Hum Mol Genet 20:2560–2570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kinane JA, Benakanakere MR, Zhao J, Hosur KB, Kinane DF (2012) Porphyromonas gingivalis influences actin degradation within epithelial cells during invasion and apoptosis. Cell Microbiol 14:1085–1096

    Article  CAS  PubMed  Google Scholar 

  58. Boesze-Battaglia K, Goldberg AF, Dispoto J, Katragadda M, Cesarone G, Albert AD (2003) A soluble peripherin/Rds C-terminal polypeptide promotes membrane fusion and changes conformation upon membrane association. Exp Eye Res 77:505–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu J, Lu W, Reigada DNJ, Laties AM, Mitchell CH (2008) Restoration of lysosomal pH in RPE cells from cultured human and ABCA4(−/−) mice: Pharmacologic approaches and functional recovery. Invest Ophthalmol Vis Sci 49:772–780

    Article  PubMed  PubMed Central  Google Scholar 

  60. Guha S, Coffey EE, Lu W, Lim JC, Beckel JM, Laties AM, Boesze-Battaglia K, Mitchell CH (2014) Approaches for detecting lysosomal alkalinization and impaired degradation in fresh and cultured RPE cells: Evidence for a role in retinal degenerations. Exp Eye Res 126:68–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from PHS; R01EY010420, R01DE022465, and R21EY018705 to KBB, R01 EY013434 to CHM, Vision Research Core Grant EY001583 (KBB and CHM) and P30EY00331 and R01EY07042 to DSW. DSW is an RPB Jules and Doris Stein Professor. The authors would like to thank Dr. Anuradha Dhingra and Mr. Frank P. Stefano for their expert technical assistance as Managers of the PDM-Live Cell Imaging Core.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kathleen Boesze-Battaglia.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Figure 1

MREG and LC3 associate with Ingested OS phagosomes. ARPE19 (C2) cells challenged with TR-OS for 2h, were washed, external fluorescence quenched with trypan blue, fixed and stained for LC3 (Cell Signaling) and labeled with anti-rabbit Alexa Fluor 488. Cells were imaged and co-distribution analyzed using a binary submask Pearson’s coefficient 0.68. panel depicts representative co-localization images at t=1h depicting association of both MREG and LC3 with ingested TR-OS. Scale bar = 10 micron (PDF 41 kb)

Supplemental Figure 2

Atg5 knockdown and rapamycin treatment of ARPE19 cells. (A) Atg5 knock down RPE cells challenged with TR-OS for 2h, were washed, external fluorescence quenched with trypan blue, fixed and stained for LC3. Cells were imaged and co-distribution analyzed using a binary submask Pearson’s coefficient 0.68. Error bars represent ± SEM, (***p<0.001). Individual channels are indicated. (B) Atg5 knockdown in ARPE19 cells. siRNA-mediated silencing of Atg5 expression detected by western blot showed 71% knockdown compared to scrambled siRNA control. (C) Atg5 knockdown or scrRNA control cells were incubated with TR-OS at a density of 10 particles/cell for 2h at 37°C. Cells were washed and processed for immunofluorescence as described in methods. TR-OS were identified and quantitated. (D) Atg5 siRNA knockdown or scrRNA RPE cells were processed for immunofluorescence as described in methods. LC3 puncta were identified and quantitated. Error bars represent ±SEM, (* p<0.01). The data are an average of three independent Atg5 knock-down experiments. Error bars represent ±SEM. (E) TR-OS co-distribution with LC3 is unaffected by rapamycin. ARPE19 cells incubated with 100nM rapamycin for 4h prior to 2h TR-OS challenge and remained in the media for the duration of the study. Cells were imaged and co-distribution analyzed using a binary submask. Individual channels are indicated. (F) Rapamycin (100nM) inhibits S6 ribosomal protein phosphorylation in ARPE19 cells. ARPE19 cells were fed 20% FBS for 30 min, kept under regular growth conditions (10% FBS), or challenged with 100nM Rapamycin for 4 or 24h. Cells were washed and cleared lysates prepared for immuno-blotting. Western blots probed with anti-phospho S6 (Cell Signaling) and anti-actin as a loading control are shown. (PDF 281 kb)

Supplemental Figure 3

(A) MREG expression in C2, M5 and M5 cells transfected with MREG, these cells are designated (R). Western blots probed with anti-MREG and anti-actin as a loading control shown. (B) POS uptake in C2, M5 and M5+MREG (R) cells. Cells were incubated with TR-OS at a density of 10 particles/cell for up to 2h at 37°C. Cells were washed and processed for immunofluorescence as described in methods. TR-OS were identified and quantitated. The data are an average of three independent experiments. Error bars represent ±SEM (C) Lysosomal pH remained acidic upon MREG knockdown. Lysosomal pH was measured as described. Error bars represent ±SEM (n=9). (PDF 141 kb)

Supplemental Figure 4

Opsin is degraded in a time-dependent manner in hfRPE cells. (A) Time course of opsin in RPE lysates from POS pulse/chase study. hfRPE cells were pulsed with POS for 20 min and phagocytosis was allowed to continue for the time points indicated, t=0h, no POS addition, t=5minute chase, t=0.5h chase and t=4h chase. RPE lysates from apical and basal chamber were collected and pooled at each time points. Proteins were separated by SDS-Page and immunoblotted with anti-opsin mAb 4D2. A representative western is shown in the inset. Western blots were quantified and opsin levels show progressive decrease over time of chase. Results are average of 3 independent experiments each analyzed in duplicate. Error bars represent ±SEM. (B) Primed hfRPE cells show normal Cathepsin D processing. Cleared cell lysates from polarized hfRPE cells were probed with anti-Cathepsin D Ab to follow Cat-D processing. (PDF 38 kb)

Supplemental Figure 5

MREG associates with LC3. (A). Immunoprecipitation (IP) studies were carried out with lysates prepared from Mreg +/+ and Mreg dsu/dsu RPE cells (6 month old animals, sacrificed 3h after light onset). Lysates(inout) for botth e antiLC3 and the MOPC1 a none specific IgG control are indicated Proteins were immunoprecipitated with a polyclonal anti-LC3 antibody and then immunoblotted (IB) anti-LC3. (B) Immunoprecipitation (IP) studies were carried out with lysates prepared from C2 and M5 RPE cells isolated either at t=0 (no OS addition, designated, −OS) or after 2h outer segment feeding (designated, +OS). The blots shown indicated the Bound (elute) and Unbound fractions (designated FT) for both anti-LC3 as well as MOPC1 control. Proteins were immunoprecipitated with a polyclonal anti-LC3 antibody and then immunoblotted (IB) using an anti-MREG mAb or anti-LC3. (C) MREG-GST pulls down LC3 from mouse RPE lysates. The lysates inputs from Mreg +/+ and Mreg dsu/dsu RPE cells (6 month old animals, sacrificed 3h after light onset) are indicated. (D) MREG does not immunoprecipitates with anti-LC3 in macrophages upon POS challenge. J774A.1 cells challenged with TR-OS for 2h at 37°C as described in methods for C2 cells. Cells were washed, lysates prepared and LC3 containing complexes were immunoprecipitated with anti-LC3 and IB probed with anti-MREG or anti-LC3. El indicates (bound fraction) and Fl indicates flow through for both anti-LC3 IP as well as MOPC1 control. (PDF 200 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frost, L.S., Lopes, V.S., 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 52, 1135–1151 (2015). https://doi.org/10.1007/s12035-014-8920-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8920-5

Keywords

Navigation