Skip to main content
SpringerLink
Log in

Alpha-Synuclein Expression in the Developing Human Brain

  • Original article
  • Published:
Pediatric and Developmental Pathology

Abstract

Alpha (α)-synuclein is a presynaptic protein, abnormal expression of which has been associated with neurodegenerative and neoplastic diseases. It is abundant in the developing vertebrate central nervous system (CNS), but less is known about its developmental expression in the human CNS. Immunohistochemical expression of α-synuclein was studied in 39 fetal, perinatal, pediatric, and adolescent brains. Perikaryal expression of α-synuclein is observed as early as 11-wk gestation in the cortical plate. Several discrete neuronal groups in the hippocampus, basal ganglia, and brain stem express perikaryal α-synuclein by 20-wk gestation, persisting through the first few years of life. In the cerebellum, α-synuclein is present by 21-wk gestation and persists into adult life as a coarse granular neuropil reaction product in the internal granular layer, and as a diffuse neuropil “blush” in the molecular layer. The germinal matrix, glia, endothelial cells, external granular layer, Pukinje cells, and dentate neurons are consistently negative for α-synuclein. We conclude that α-synuclein is expressed very early in human gestation, and that its distribution and temporal sequence of expression varies in discrete neuronal groups. Perikaryal α-synuclein starts disappearing from the neuronal cytosol in early childhood, and only the neuropil retains immunoreactivity into adulthood. The reappearance of α-synuclein in the adult neuronal cytosol in certain disease processes may represent reemergence of cues from an earlier developmental stage as part of a stress response.

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

Figure 1.
Figure 2.
Figure 3.
Figure 4.

Similar content being viewed by others

References

  1. R Jakes MG Spillantini M Goedert (1994) ArticleTitleIdentification of two distinct synucleins from human brain FEBS Lett 345 27–32 Occurrence Handle1:CAS:528:DyaK2cXlslehtb4%3D Occurrence Handle10.1016/0014-5793(94)00395-5 Occurrence Handle8194594

    Article  CAS  PubMed  Google Scholar 

  2. DF Clayton JM George (1998) ArticleTitleThe synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease Trends Neurosci 21 249–254 Occurrence Handle1:CAS:528:DyaK1cXjs1Kms78%3D Occurrence Handle10.1016/S0166-2236(97)01213-7 Occurrence Handle9641537

    Article  CAS  PubMed  Google Scholar 

  3. C Lavedan (1998) ArticleTitleThe synuclein family Genome Res 8 871–880 Occurrence Handle1:CAS:528:DyaK1cXmsVWgsro%3D Occurrence Handle9750188

    CAS  PubMed  Google Scholar 

  4. A Surguchov I Surgucheva E Solessio W Baehr (1999) ArticleTitleSynoretin—a new protein belonging to the synuclein family Mol Cell Neurosci 13 95–103 Occurrence Handle1:CAS:528:DyaK1MXisFGjt7g%3D Occurrence Handle10.1006/mcne.1999.0735 Occurrence Handle10192768

    Article  CAS  PubMed  Google Scholar 

  5. MH Polymeropoulos C Lavedan E Leroy et al. (1997) ArticleTitleMutation in the alpha-synuclein gene identified in families with Parkinson’s disease Science 276 2045–2047 Occurrence Handle1:CAS:528:DyaK2sXkt1altr4%3D Occurrence Handle10.1126/science.276.5321.2045 Occurrence Handle9197268

    Article  CAS  PubMed  Google Scholar 

  6. T Arai K Ueda K Ikeda et al. (1999) ArticleTitleArgyrophilic glial inclusions in the midbrain of patients with Parkinson’s disease and diffuse Lewy body disease are immunopositive for NACP/alpha-synuclein Neurosci Lett 259 83–86 Occurrence Handle1:CAS:528:DyaK1cXotVKit7k%3D Occurrence Handle10.1016/S0304-3940(98)00890-8 Occurrence Handle10025563

    Article  CAS  PubMed  Google Scholar 

  7. G Forloni I Bertani AM Calella F Thaler R Invernizzi (2000) ArticleTitleAlpha-synuclein and Parkinson’s disease: selective neurodegenerative effect of alpha-synuclein fragment on dopaminergic neurons in vitro and in vivo Ann Neurol 47 632–640 Occurrence Handle1:CAS:528:DC%2BD3cXjsFCntrg%3D Occurrence Handle10.1002/1531-8249(200005)47:5<632::AID-ANA11>3.0.CO;2-N Occurrence Handle10805334

    Article  CAS  PubMed  Google Scholar 

  8. JE Galvin K Uryu VM Lee JQ Trojanowski (1999) ArticleTitleAxon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein Proc Natl Acad Sci USA 96 13450–13455 Occurrence Handle1:CAS:528:DyaK1MXns1Gmur4%3D Occurrence Handle10.1073/pnas.96.23.13450 Occurrence Handle10557341 Occurrence Handle23968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. E Mezey A Dehejia G Harta MI Papp MH Polymeropoulos MJ Brownstein (1998) ArticleTitleAlpha synuclein in neurodegenerative disorders: murderer or accomplice Nat Med 4 755–757 Occurrence Handle1:CAS:528:DyaK1cXktlKgsL8%3D Occurrence Handle10.1038/nm0798-755 Occurrence Handle9662355

    Article  CAS  PubMed  Google Scholar 

  10. A Takeda M Mallory M Sundsmo W Honer L Hansen E Masliah (1998) ArticleTitleAbnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders Am J Pathol 152 367–372 Occurrence Handle1:STN:280:DyaK1c7is1Sgug%3D%3D Occurrence Handle9466562 Occurrence Handle1857971

    CAS  PubMed  PubMed Central  Google Scholar 

  11. A Takeda M Hashimoto M Mallory M Sundsumo L Hansen E Masliah (2000) ArticleTitleC-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders Acta Neuropathol (Berl) 99 296–304 Occurrence Handle1:CAS:528:DC%2BD3cXms1Cqug%3D%3D Occurrence Handle10.1007/PL00007441

    Article  CAS  Google Scholar 

  12. W Bruening BI Giasson AJ Klein-Szanto VM Lee JQ Trojanowski AK Godwin (2000) ArticleTitleSynucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary Cancer 88 2154–2163 Occurrence Handle1:CAS:528:DC%2BD3cXjtF2mu7o%3D Occurrence Handle10.1002/(SICI)1097-0142(20000501)88:9<2154::AID-CNCR23>3.0.CO;2-9 Occurrence Handle10813729

    Article  CAS  PubMed  Google Scholar 

  13. M Kawashima SO Suzuki K Doh-ura T Iwaki (2000) ArticleTitleAlpha-synuclein is expressed in a variety of brain tumors showing neuronal differentiation Acta Neuropathol (Berl) 99 154–160 Occurrence Handle1:CAS:528:DC%2BD3cXosVSn Occurrence Handle10.1007/PL00007419

    Article  CAS  Google Scholar 

  14. R Raghavan CL White SuffixIII B Rogers C Coimbra EJ Rushing (2000) ArticleTitleAlpha-synuclein expression in central nervous system tumors showing neuronal or mixed neuronal/glial differentiation J Neuropathol Exp Neurol 59 490–494 Occurrence Handle1:CAS:528:DC%2BD3cXktlWrtbo%3D Occurrence Handle10.1093/jnen/59.6.490 Occurrence Handle10850861

    Article  CAS  PubMed  Google Scholar 

  15. DF Clayton JM George (1999) ArticleTitleSynucleins in synaptic plasticity and neurodegenerative disorders J Neurosci Res 58 120–129 Occurrence Handle1:CAS:528:DyaK1MXmtl2gsb8%3D Occurrence Handle10.1002/(SICI)1097-4547(19991001)58:1<120::AID-JNR12>3.0.CO;2-E Occurrence Handle10491577

    Article  CAS  PubMed  Google Scholar 

  16. DD Murphy SM Rueter JQ Trojanowski VM Lee (2000) ArticleTitleSynucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons J Neurosci 20 3214–3220 Occurrence Handle1:CAS:528:DC%2BD3cXivFKhtL4%3D Occurrence Handle10777786

    CAS  PubMed  Google Scholar 

  17. JM George H Jin WS Woods DF Clayton (1995) ArticleTitleCharacterization of a novel protein regulated during the critical period for song learning in the zebra finch Neuron 15 361–372 Occurrence Handle1:CAS:528:DyaK2MXnvVWlsbc%3D Occurrence Handle10.1016/0896-6273(95)90040-3 Occurrence Handle7646890

    Article  CAS  PubMed  Google Scholar 

  18. A Iwai E Masliah M Yoshimoto et al. (1995) ArticleTitleThe precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system Neuron 14 467–475 Occurrence Handle1:CAS:528:DyaK2MXjvFejsLY%3D Occurrence Handle10.1016/0896-6273(95)90302-X Occurrence Handle7857654

    Article  CAS  PubMed  Google Scholar 

  19. TA Bayer P Jakala T Hartmann et al. (1999) ArticleTitleNeural expression profile of alpha-synuclein in developing human cortex Neuroreport 10 2799–2803 Occurrence Handle1:STN:280:DyaK1MvjvFClsw%3D%3D Occurrence Handle10.1097/00001756-199909090-00019 Occurrence Handle10511443

    Article  CAS  PubMed  Google Scholar 

  20. JE Galvin TM Schuck VM Lee JQ Trojanowski (2001) ArticleTitleDifferential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigra Exp Neurol 168 347–355 Occurrence Handle1:CAS:528:DC%2BD3MXhvFKjsb8%3D Occurrence Handle10.1006/exnr.2000.7615 Occurrence Handle11259122

    Article  CAS  PubMed  Google Scholar 

  21. L Hong HW Ko BJ Gwag et al. (1998) ArticleTitleThe cDNA cloning and ontogeny of mouse alpha-synuclein Neuroreport 9 1239–1243 Occurrence Handle1:CAS:528:DyaK1cXjtFaktrw%3D Occurrence Handle10.1097/00001756-199804200-00051 Occurrence Handle9601701

    Article  CAS  PubMed  Google Scholar 

  22. LJ Hsu M Mallory Y Xia et al. (1998) ArticleTitleExpression pattern of synucleins (non-A beta component of Alzheimer’s disease amyloid precursor protein/alpha-synuclein) during murine brain development J Neurochem 71 338–344 Occurrence Handle1:CAS:528:DyaK1cXktFamtro%3D Occurrence Handle10.1046/j.1471-4159.1998.71010338.x Occurrence Handle9648883

    Article  CAS  PubMed  Google Scholar 

  23. K Petersen OF Olesen JD Mikkelsen (1999) ArticleTitleDevelopmental expression of alpha-synuclein in rat hippocampus and cerebral cortex Neuroscience 91 651–659 Occurrence Handle1:CAS:528:DyaK1MXivFKmsb0%3D Occurrence Handle10.1016/S0306-4522(98)00596-X Occurrence Handle10366022

    Article  CAS  PubMed  Google Scholar 

  24. AA Tiunova KV Anokhin AR Saha et al. (2000) ArticleTitleChicken synucleins: cloning and expression in the developing embryo Mech Dev 99 195–198 Occurrence Handle1:CAS:528:DC%2BD3cXot1yitL8%3D Occurrence Handle10.1016/S0925-4773(00)00484-6 Occurrence Handle11091093

    Article  CAS  PubMed  Google Scholar 

  25. JJ Kepes J Collins (1999) ArticleTitleChoroid plexus epithelium (normal and neoplastic) expresses synaptophysin. A potentially useful aid in differentiating carcinoma of the choroid plexus from metastatic papillary carcinomas J Neuropathol Exp Neurol 58 398–401 Occurrence Handle1:STN:280:DyaK1M3jtlSjsQ%3D%3D Occurrence Handle10.1097/00005072-199904000-00010 Occurrence Handle10218635

    Article  CAS  PubMed  Google Scholar 

  26. M Ohta T Kitamoto T Iwaki T Ohgami M Fukui J Tateishi (1993) ArticleTitleImmunohistochemical distribution of amyloid precursor protein during normal rat development Brain Res Dev Brain Res 75 151–161 Occurrence Handle1:CAS:528:DyaK3sXmsVKms78%3D Occurrence Handle10.1016/0165-3806(93)90019-7 Occurrence Handle7505208

    Article  CAS  PubMed  Google Scholar 

  27. A Abeliovich Y Schmitz I Farinas et al. (2000) ArticleTitleMice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system Neuron 25 239–252 Occurrence Handle1:CAS:528:DC%2BD3cXhtVWrt74%3D Occurrence Handle10.1016/S0896-6273(00)80886-7 Occurrence Handle10707987

    Article  CAS  PubMed  Google Scholar 

  28. B Sommer S Barbieri K Hofele et al. (2000) ArticleTitleMouse models of alpha-synucleinopathy and Lewy pathology Exp Gerontol 35 1389–1403 Occurrence Handle1:CAS:528:DC%2BD3cXoslGgu7c%3D Occurrence Handle10.1016/S0531-5565(00)00181-9 Occurrence Handle11113617

    Article  CAS  PubMed  Google Scholar 

  29. A Kenessey SH Yen (1993) ArticleTitleThe extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments Brain Res 629 40–46 Occurrence Handle1:CAS:528:DyaK2cXnsVOitg%3D%3D Occurrence Handle10.1016/0006-8993(93)90478-6 Occurrence Handle8287279

    Article  CAS  PubMed  Google Scholar 

  30. SM Jenkins GV Johnson (1997) ArticleTitlePhosphorylation of microtubule-associated protein tau on Ser 262 by an embryonic 100 kDa protein kinase Brain Res 767 305–313 Occurrence Handle1:CAS:528:DyaK2sXltl2ltL4%3D Occurrence Handle10.1016/S0006-8993(97)00615-X Occurrence Handle9367262

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

We are grateful to Dennis Burns, MD, Autopsy Service Director, Parkland Memorial Hospital, Jeffery Barnard, MD, Chief Medical Examiner, Dallas, TX; and the Pathology staff at the Children’s Medical Center of Dallas, for providing case material for this study. Linda S. Hynan, Academic Computing Services, UTSW Medical Center, Dallas, helped us with statistical analysis. This research was supported in part by NIH Alzheimer Disease Center grant AG12300.

Author information

Authors and Affiliations

  1. Neuropathology Laboratory, Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9073, USA

    Ravi Raghavan, Loes de Kruijff, Monique D. Sterrenburg & Charles L. White III

  2. Immunohistochemistry Laboratory, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Christa L. Hladik & Charles L. White III

  3. Department of Pathology, Children’s Medical Center, Dallas, TX, USA

    Beverly B. Rogers

Authors
  1. Ravi Raghavan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Loes de Kruijff
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monique D. Sterrenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beverly B. Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christa L. Hladik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charles L. White III
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ravi Raghavan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Raghavan, R., Kruijff, L., Sterrenburg, M. et al. Alpha-Synuclein Expression in the Developing Human Brain. Pediatr Dev Pathol 7, 506–516 (2004). https://doi.org/10.1007/s10024-003-7080-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10024-003-7080-9

Search

Navigation