Skip to main content

Advertisement

SpringerLink
Log in

Ras Homolog Enriched in the Brain is Linked to Retinal Ganglion Cell Apoptosis after Light Injury in Rats

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Ras homolog enriched in the brain (Rheb) is a small GTPase of the Ras family. It has been confirmed that Rheb activation not only regulates cell growth and migration but also induces neuron apoptosis after toxic stimuli. However, the function of Rheb in the retina is still not fully understood. To find out whether Rheb was involved in retinal neuron death, the expression profile of Rheb in light-damaged retinal ganglion cells (RGCs) of adult rats was investigated. Western blotting showed the expression of Rheb was significantly upregulated in the injured retina. Rheb was mainly detected in apoptotic RGCs by using double immunofluorescent staining. Active caspase-3 was upregulated and co-labeled with Rheb. Meanwhile, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) showed that Rheb-positive RGCs underwent apoptosis after light exposure, which suggested that Rheb might be relevant to RGC apoptosis following phototoxicity. Furthermore, Western blotting and immunofluorescence showed that the expression profiles of CyclinD1 and cyclin-dependent kinase 4 (CDK4) were parallel with that of Rheb in a time–space dependent manner. Based on this study, it is speculated that Rheb might play an important role in physiological and pathological process in light-induced retina damage, which might provide a potential therapeutic avenue of retinal degeneration.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  • Arakawa-Takeuchi S, Kobayashi K, Park JH, Uranbileg B, Yamamoto H, Jinno S, Okayama H (2010) Mammalian target of rapamycin complex 1 signaling opposes the effects of anchorage loss, leading to activation of Cdk4 and Cdc6 stabilization. FEBS Lett 584:2779–2785

    Article  CAS  PubMed  Google Scholar 

  • Arnault E, Barrau C, Nanteau C, Gondouin P, Bigot K, Vienot F, Gutman E, Fontaine V, Villette T, Cohen-Tannoudji D, Sahel JA, Picaud S (2013) Phototoxic action spectrum on a retinal pigment epithelium model of age-related macular degeneration exposed to sunlight normalized conditions. PLoS One 8:e71398

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Augood CA, Vingerling JR, de Jong PT, Chakravarthy U, Seland J, Soubrane G, Tomazzoli L, Topouzis F, Bentham G, Rahu M, Vioque J, Young IS, Fletcher AE (2006) Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Arch Ophthalmol 124:529–535

    Article  PubMed  Google Scholar 

  • Becker EB, Bonni A (2004) Cell cycle regulation of neuronal apoptosis in development and disease. Prog Neurobiol 72:1–25

    Article  CAS  PubMed  Google Scholar 

  • Cao M, Tan X, Jin W, Zheng H, Xu W, Rui Y, Li L, Cao J, Wu X, Cui G, Ke K, Gao Y (2013) Upregulation of Ras homolog enriched in the brain (Rheb) in lipopolysaccharide-induced neuroinflammation. Neurochem Int 62:406–417

    Article  CAS  PubMed  Google Scholar 

  • Chahory S, Padron L, Courtois Y, Torriglia A (2004) The LEI/L-DNase II pathway is activated in light-induced retinal degeneration in rats. Neurosci Lett 367:205–209

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Song Y, Yao J, Weng C, Yin ZQ (2013) Alterations of sodium and potassium channels of RGCs in RCS rat with the development of retinal degeneration. J Mol Neurosci 51(3):976–985

    Article  CAS  PubMed  Google Scholar 

  • Dejda A, Jolivel V, Bourgault S, Seaborn T, Fournier A, Vaudry H, Vaudry D (2008) Inhibitory effect of PACAP on caspase activity in neuronal apoptosis: a better understanding towards therapeutic applications in neurodegenerative diseases. J Mol Neurosci 36:26–37

    Article  CAS  PubMed  Google Scholar 

  • Donovan M, Carmody RJ, Cotter TG (2001) Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3-independent. J Biol Chem 276:23000–23008

    Article  CAS  PubMed  Google Scholar 

  • Fletcher AE, Bentham GC, Agnew M, Young IS, Augood C, Chakravarthy U, de Jong PT, Rahu M, Seland J, Soubrane G, Tomazzoli L, Topouzis F, Vingerling JR, Vioque J (2008) Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol 126:1396–1403

    Article  PubMed  Google Scholar 

  • Friedman DS, O'Colmain BJ, Munoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P, Kempen J, Eye Diseases Prevalence Research G (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122:564–572

    Article  PubMed  Google Scholar 

  • Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11:1457–1466

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Ayuso D, Salinas-Navarro M, Agudo-Barriuso M, Alarcon-Martinez L, Vidal-Sanz M, Villegas-Perez MP (2011) Retinal ganglion cell axonal compression by retinal vessels in light-induced retinal degeneration. Mol Vis 17:1716–1733

    PubMed Central  PubMed  Google Scholar 

  • Harris TE, Lawrence JC Jr (2003) TOR signaling. Sci STKE 2003:re15

    PubMed  Google Scholar 

  • Hevroni D, Rattner A, Bundman M, Lederfein D, Gabarah A, Mangelus M, Silverman MA, Kedar H, Naor C, Kornuc M, Hanoch T, Seger R, Theill LE, Nedivi E, Richter-Levin G, Citri Y (1998) Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms. J Mol Neurosci 10:75–98

    Article  CAS  PubMed  Google Scholar 

  • 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 Central  PubMed  Google Scholar 

  • Karassek S, Berghaus C, Schwarten M, Goemans CG, Ohse N, Kock G, Jockers K, Neumann S, Gottfried S, Herrmann C, Heumann R, Stoll R (2010) Ras homolog enriched in brain (Rheb) enhances apoptotic signaling. J Biol Chem 285:33979–33991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Katai N, Yoshimura N (1999) Apoptotic retinal neuronal death by ischemia-reperfusion is executed by two distinct caspase family proteases. Invest Ophthalmol Vis Sci 40:2697–2705

    CAS  PubMed  Google Scholar 

  • Kermer P, Klocker N, Labes M, Thomsen S, Srinivasan A, Bahr M (1999) Activation of caspase-3 in axotomized rat retinal ganglion cells in vivo. FEBS Lett 453:361–364

    Article  CAS  PubMed  Google Scholar 

  • Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, Emokpae R Jr, Gorospe M, Mattson MP (2004) Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41:549–561

    Article  CAS  PubMed  Google Scholar 

  • Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY (2012) Age-related macular degeneration. Lancet 379:1728–1738

    Article  PubMed  Google Scholar 

  • Liu DX, Greene LA (2001) Neuronal apoptosis at the G1/S cell cycle checkpoint. Cell Tissue Res 305:217–228

    Article  CAS  PubMed  Google Scholar 

  • Marc RE, Jones BW, Watt CB, Vazquez-Chona F, Vaughan DK, Organisciak DT (2008) Extreme retinal remodeling triggered by light damage: implications for age related macular degeneration. Mol Vis 14:782–806

    PubMed Central  PubMed  Google Scholar 

  • Marco-Gomariz MA, Hurtado-Montalban N, Vidal-Sanz M, Lund RD, Villegas-Perez MP (2006) Phototoxic-induced photoreceptor degeneration causes retinal ganglion cell degeneration in pigmented rats. J Comp Neurol 498:163–179

    Article  CAS  PubMed  Google Scholar 

  • Men J, Zhang X, Yang Y, Gao D (2012) An AD-related neuroprotector rescues transformed rat retinal ganglion cells from CoCl(2)-induced apoptosis. J Mol Neurosci 47:144–149

    Article  CAS  PubMed  Google Scholar 

  • Nie D, Di Nardo A, Han JM, Baharanyi H, Kramvis I, Huynh T, Dabora S, Codeluppi S, Pandolfi PP, Pasquale EB, Sahin M (2010) Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci 13:163–172

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Organisciak DT, Vaughan DK (2010) Retinal light damage: mechanisms and protection. Prog Retin Eye Res 29:113–134

    Article  PubMed Central  PubMed  Google Scholar 

  • Osuga H, Osuga S, Wang F, Fetni R, Hogan MJ, Slack RS, Hakim AM, Ikeda JE, Park DS (2000) Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci U S A 97:10254–10259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Parrales A, López E, Lee-Rivera I, López-Colomé AM (2013) ERK1/2-dependent activation of mTOR/mTORC1/p70S6K regulates thrombin-induced RPE cell proliferation. Cell Signal 25(4):829–838

    Article  CAS  PubMed  Google Scholar 

  • Peng Y, Zhang J, Xu H, He J, Ying X, Wang Y (2013) Neuroprotective effect of protease-activated receptor-2 in the hypoxia-induced apoptosis of rat RGC-5 cells. J Mol Neurosci 50:98–108

    Article  CAS  PubMed  Google Scholar 

  • Randazzo J, Zhang Z, Hoff M, Kawada H, Sachs A, Yuan Y, Haider N, Kador P (2011) Orally active multi-functional antioxidants are neuroprotective in a rat model of light-induced retinal damage. PLoS One 6:e21926

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rein DB, Wittenborn JS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J, Vision Health Cost-Effectiveness Study, G (2009) Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol 127:533–540

    Article  PubMed  Google Scholar 

  • Ru W, Peng Y, Zhong L, Tang SJ (2012) A role of the mammalian target of rapamycin (mTOR) in glutamate-induced down-regulation of tuberous sclerosis complex proteins 2 (TSC2). J Mol Neurosci 47:340–345

    Article  CAS  PubMed  Google Scholar 

  • Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734

    Article  CAS  PubMed  Google Scholar 

  • Saito K, Araki Y, Kontani K, Nishina H, Katada T (2005) Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem 137:423–430

    Article  CAS  PubMed  Google Scholar 

  • Schwartz EI, Smilenov LB, Price MA, Osredkar T, Baker RA, Ghosh S, Shi FD, Vollmer TL, Lencinas A, Stearns DM, Gorospe M, Kruman II (2007) Cell cycle activation in postmitotic neurons is essential for DNA repair. Cell Cycle 6:318–329

    Article  CAS  PubMed  Google Scholar 

  • Seddon JM, Reynolds R, Yu Y, Daly MJ, Rosner B (2011) Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology 118:2203–2211

    Article  PubMed Central  PubMed  Google Scholar 

  • Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, Hofman A, Jensen S, Wang JJ, de Jong PT (2001) Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 108:697–704

    Article  CAS  PubMed  Google Scholar 

  • Sparrow JR, Cai B (2001) Blue light-induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl-2. Invest Ophthalmol Vis Sci 42(6):1356–1362

    CAS  PubMed  Google Scholar 

  • Springer JE, Nottingham SA, McEwen ML, Azbill RD, Jin Y (2001) Caspase-3 apoptotic signaling following injury to the central nervous system. Clin Chem Lab Med 39:299–307

    Article  CAS  PubMed  Google Scholar 

  • Steindl-Kuscher K, Krugluger W, Boulton ME, Haas P, Schrattbauer K, Feichtinger H, Adlassnig W, Binder S (2009) Activation of the beta-catenin signaling pathway and its impact on RPE cell cycle. Invest Ophthalmol Vis Sci 50(9):4471–4476. doi:10.1167/iovs.08-3139

    Article  PubMed  Google Scholar 

  • Wang T, Lao U, Edgar BA (2009) TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol 186:703–711

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu Y, Yang L, et al. Spatiotemporal Changes in NFATc4 expression of retinal ganglion cells after light-induced damage. J Mol Neurosci. (2013); doi 10.1007/s12031-013-0198-y

  • Yang Y, Mufson EJ, Herrup K (2003) Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J Neurosci 23:2557–2563

    CAS  PubMed  Google Scholar 

  • Young RW (1987) Pathophysiology of age-related macular degeneration. Surv Ophthalmol 31:291–306

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Xu G, Liu W, Ni Y, Zhou W (2012) Role of fractalkine/CX3CR1 interaction in light-induced photoreceptor degeneration through regulating retinal microglial activation and migration. PLoS One 7:e35446

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zou J, Zhou L, Du XX, Ji Y, Xu J, Tian J, Jiang W, Zou Y, Yu S, Gan L, Luo M, Yang Q, Cui Y, Yang W, Xia X, Chen M, Zhao X, Shen Y, Chen PY, Worley PF, Xiao B (2011) Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev Cell 20:97–108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by the National Key Basic Research Program of China (2013CB967503), National Natural Science Foundation of China (Grant No. NSFC 81170857), National Science and Technology Major Project (2011ZX09302-007-02) and Youth project of National Natural Science Fund (2013,81300780). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of Interest

The authors claim no conflicts of interest.

Financial Disclosure

None to declare.

Author information

Authors and Affiliations

  1. Department of Ophthalmology and Vision Sciences and Key Laboratory of Myopia of State Health Ministry, Eye and ENT Hospital, Shanghai Medical College, Fudan University, No.83 Fenyang Road, Shanghai, People’s Republic of China

    Qinmeng Shu, Hong Zhuang, Jiawen Fan, Zhongcui Sun, Meng Zhang & Gezhi Xu

  2. Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, People’s Republic of China

    Qinmeng Shu, Hong Zhuang, Jiawen Fan, Zhongcui Sun, Meng Zhang & Gezhi Xu

  3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China

    Yue Xu

Authors
  1. Qinmeng Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiawen Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhongcui Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gezhi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gezhi Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shu, Q., Xu, Y., Zhuang, H. et al. Ras Homolog Enriched in the Brain is Linked to Retinal Ganglion Cell Apoptosis after Light Injury in Rats. J Mol Neurosci 54, 243–251 (2014). https://doi.org/10.1007/s12031-014-0281-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-014-0281-z

Keywords

Search

Navigation