Differential Gamma-Synuclein Expression in Acute and Chronic Retinal Ganglion Cell Death in the Retina and Optic Nerve

  • Yuan Liu
  • Mary L. Tapia
  • Justin Yeh
  • Rossana Cheng He
  • Dustin Pomerleu
  • Richard K. LeeEmail author
Original Article


We used genetic naturally occurring glaucoma (DBA/2J) and experimentally induced optic nerve crush (ONC) as models to study gamma-synuclein expression change in retinal ganglion cells and optic nerves. Gene chip microarray analysis demonstrated downregulated expression of the gamma-synuclein gene in DBA/2J mice as they developed age-associated glaucoma with concomitant with retinal ganglion cell loss. Real-time PCR, Western blot, and immunostaining results confirmed that the expression of gamma-synuclein at the mRNA and protein level was significantly reduced in the retinas and optic nerves of aged DBA/2J mice. We also observed similar reduced expression of gamma-synuclein in the retinas from mice after optic nerve crush. Surprisingly, the expression of gamma-synuclein was increased in optic nerves after crush. This is the first study demonstrating gamma-synuclein-expressing cells accumulate in the optic nerve crush site. Gamma-synuclein was found in axons colocalizing largely with neurofilaments in control mice without injury but was found inside cells within the scar in the crush site. Gamma-synuclein expression is predominantly expressed at the optic nerve crush site associated with CD68+ macrophage-like cells, not GFAP-expressing astroglial cells, suggesting gamma-synuclein expression is associated with glial scar formation inhibitory to optic nerve regeneration. We propose gamma-synuclein labels macrophage-like cells recruited to the site of acute optic nerve injury.


Gamma-synuclein DBA/2J Optic nerve crush Macrophage Scar formation 


Funding Information

The Bascom Palmer Eye Institute is supported by the NIH Center Core Grant P30EY014801 and a Research to Prevent Blindness Unrestricted Grant. R.K. Lee is supported by the Walter G. Ross Foundation. This work was partially supported by the Guitierrez Family Research Fund and a research gift from the Vakil family.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Statement on the Welfare of Animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice of the University of Miami Institutional Animal Care and Use Committee.

Supplementary material

12035_2019_1735_MOESM1_ESM.docx (901 kb)
ESM 1 (DOCX 900 kb).


  1. 1.
    George, J.M. 2002. The synucleins. Genome Biol. 3:REVIEWS3002.Google Scholar
  2. 2.
    Surgucheva I, Surguchov A (2008) Gamma-synuclein: cell-type-specific promoter activity and binding to transcription factors. J Mol Neurosci 35:267–271CrossRefPubMedGoogle Scholar
  3. 3.
    Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252CrossRefPubMedGoogle Scholar
  4. 4.
    Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–1667CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Oaks AW, Sidhu A (2011) Synuclein modulation of monoamine transporters. FEBS Lett 585:1001–1006CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Snyder H, Mensah K, Hsu C, Hashimoto M, Surgucheva IG, Festoff B, Surguchov A, Masliah E et al (2005) beta-Synuclein reduces proteasomal inhibition by alpha-synuclein but not gamma-synuclein. J Biol Chem 280:7562–7569CrossRefPubMedGoogle Scholar
  7. 7.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT et al (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108CrossRefPubMedGoogle Scholar
  9. 9.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J et al (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173CrossRefGoogle Scholar
  10. 10.
    Uversky VN, Li J, Souillac P, Millett IS, Doniach S, Jakes R, Goedert M, Fink AL (2002) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem 277:11970–11978CrossRefPubMedGoogle Scholar
  11. 11.
    Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G, Joseph BK, Rosen C et al (1997) Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 57:759–764PubMedGoogle Scholar
  12. 12.
    Jia T, Liu YE, Liu J, Shi YE (1999) Stimulation of breast cancer invasion and metastasis by synuclein gamma. Cancer Res 59:742–747PubMedGoogle Scholar
  13. 13.
    Galvin JE, Uryu K, Lee VM, Trojanowski JQ (1999) Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc Natl Acad Sci USA 96:13450–13455CrossRefPubMedGoogle Scholar
  14. 14.
    Ninkina N, Peters O, Millership S, Salem H, van der Putten H, Buchman VL (2009) Gamma-synucleinopathy: neurodegeneration associated with overexpression of the mouse protein. Hum Mol Genet 18:1779–1794CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Doherty J, McIntosh G, Milton I (2008) Alpha- and gamma-synuclein proteins are present in cerebrospinal fluid and are increased in aged subjects with neurodegenerative and vascular changes. Dement Geriatr Cogn Disord 26(1):32–42CrossRefPubMedGoogle Scholar
  16. 16.
    Surgucheva I, Shestopalov VI, Surguchov A (2008) Effect of gamma-synuclein silencing on apoptotic pathways in retinal ganglion cells. J Biol Chem 283:36377–36385CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zhang H, Kouadio A, Cartledge D, Godwin AK (2011) Role of gamma-synuclein in microtubule regulation. Exp Cell Res 317:1330–1339CrossRefPubMedGoogle Scholar
  18. 18.
    Kokhan et al (2013) Differential involvement of the gamma-synuclein in cognitive abilities on the model of knockout mice. BMC Neurosci 14:53CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY (2014) Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121:2081–2090CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Surgucheva I, McMahan B, Ahmed F, Tomarev S, Wax MB, Surguchov A (2002) Synucleins in glaucoma: implication of gamma-synuclein in glaucomatous alterations in the optic nerve. J Neurosci Res 68:97–106CrossRefPubMedGoogle Scholar
  22. 22.
    Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L et al (2008) Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322:963–966CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Munguba GC, Geisert EE, Williams RW, Tapia ML, Lam DK, Bhattacharya SK, Lee RK (2013) Effects of glaucoma on Chrna6 expression in the retina. Curr Eye Res 38:150–157CrossRefPubMedGoogle Scholar
  24. 24.
    John SW, Smith RS, Savinova OV, Hawes NL, Chang B, Turnbull D, Davisson M, Roderick TH et al (1998) Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci 39:951–962PubMedGoogle Scholar
  25. 25.
    Clayton DF, George JM (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58:120–129CrossRefPubMedGoogle Scholar
  26. 26.
    Martinez-Navarrete GC, Martin-Nieto J, Esteve-Rudd J, Angulo A, Cuenca N (2007) Alpha synuclein gene expression profile in the retina of vertebrates. Mol Vis 13:949–961PubMedPubMedCentralGoogle Scholar
  27. 27.
    Surguchov A, McMahan B, Masliah E, Surgucheva I (2001) Synucleins in ocular tissues. J Neurosci Res 65:68–77CrossRefPubMedGoogle Scholar
  28. 28.
    Lashuel HA, Overk CR, Oueslati A, Masliah E (2013) The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14:38–48CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kanda S, Bishop JF, Eglitis MA, Yang Y, Mouradian MM (2000) Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience 97:279–284CrossRefPubMedGoogle Scholar
  30. 30.
    Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156CrossRefPubMedGoogle Scholar
  31. 31.
    Buchman VL, Hunter HJ, Pinon LG, Thompson J, Privalova EM, Ninkina NN, Davies AM (1998) Persyn, a member of the synuclein family, has a distinct pattern of expression in the developing nervous system. J Neurosci 18:9335–9341CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Surgucheva IG, Sivak JM, Fini ME, Palazzo RE, Surguchov AP (2003) Effect of gamma-synuclein overexpression on matrix metalloproteinases in retinoblastoma Y79 cells. Arch Biochem Biophys 410:167–176CrossRefPubMedGoogle Scholar
  33. 33.
    Chintala SK, Zhang X, Austin JS, Fini ME (2002) Deficiency in matrix metalloproteinase gelatinase B (MMP-9) protects against retinal ganglion cell death after optic nerve ligation. J Biol Chem 277:47461–47468CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Bascom Palmer Eye InstituteUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Icahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Eye Surgery AssociatesVermont South Medical CentreVermont SouthAustralia

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