Pediatric and Developmental Pathology

, Volume 7, Issue 5, pp 506–516 | Cite as

Alpha-Synuclein Expression in the Developing Human Brain

  • Ravi Raghavan
  • Loes de Kruijff
  • Monique D. Sterrenburg
  • Beverly B. Rogers
  • Christa L. Hladik
  • Charles L. WhiteIII
Original article


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.

Key words: α-synuclein brain development fetal neurodegeneration ontogeny 


  1. 1.
    Jakes, R, Spillantini, MG, Goedert, M 1994Identification of two distinct synucleins from human brainFEBS Lett3452732CrossRefPubMedGoogle Scholar
  2. 2.
    Clayton, DF, George, JM 1998The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and diseaseTrends Neurosci21249254CrossRefPubMedGoogle Scholar
  3. 3.
    Lavedan, C 1998The synuclein familyGenome Res8871880PubMedGoogle Scholar
  4. 4.
    Surguchov, A, Surgucheva, I, Solessio, E, Baehr, W 1999Synoretin—a new protein belonging to the synuclein familyMol Cell Neurosci1395103CrossRefPubMedGoogle Scholar
  5. 5.
    Polymeropoulos, MH, Lavedan, C, Leroy, E,  et al. 1997Mutation in the alpha-synuclein gene identified in families with Parkinson’s diseaseScience27620452047CrossRefPubMedGoogle Scholar
  6. 6.
    Arai, T, Ueda, K, Ikeda, K,  et al. 1999Argyrophilic glial inclusions in the midbrain of patients with Parkinson’s disease and diffuse Lewy body disease are immunopositive for NACP/alpha-synucleinNeurosci Lett2598386CrossRefPubMedGoogle Scholar
  7. 7.
    Forloni, G, Bertani, I, Calella, AM, Thaler, F, Invernizzi, R 2000Alpha-synuclein and Parkinson’s disease: selective neurodegenerative effect of alpha-synuclein fragment on dopaminergic neurons in vitro and in vivoAnn Neurol47632640CrossRefPubMedGoogle Scholar
  8. 8.
    Galvin, JE, Uryu, K, Lee, VM, Trojanowski, JQ 1999Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synucleinProc Natl Acad Sci USA961345013455CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mezey, E, Dehejia, A, Harta, G, Papp, MI, Polymeropoulos, MH, Brownstein, MJ 1998Alpha synuclein in neurodegenerative disorders: murderer or accompliceNat Med4755757CrossRefPubMedGoogle Scholar
  10. 10.
    Takeda, A, Mallory, M, Sundsmo, M, Honer, W, Hansen, L, Masliah, E 1998Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disordersAm J Pathol152367372PubMedPubMedCentralGoogle Scholar
  11. 11.
    Takeda, A, Hashimoto, M, Mallory, M, Sundsumo, M, Hansen, L, Masliah, E 2000C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disordersActa Neuropathol (Berl)99296304CrossRefGoogle Scholar
  12. 12.
    Bruening, W, Giasson, BI, Klein-Szanto, AJ, Lee, VM, Trojanowski, JQ, Godwin, AK 2000Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovaryCancer8821542163CrossRefPubMedGoogle Scholar
  13. 13.
    Kawashima, M, Suzuki, SO, Doh-ura, K, Iwaki, T 2000Alpha-synuclein is expressed in a variety of brain tumors showing neuronal differentiationActa Neuropathol (Berl)99154160CrossRefGoogle Scholar
  14. 14.
    Raghavan, R, White, CL,III, Rogers, B, Coimbra, C, Rushing, EJ 2000Alpha-synuclein expression in central nervous system tumors showing neuronal or mixed neuronal/glial differentiationJ Neuropathol Exp Neurol59490494CrossRefPubMedGoogle Scholar
  15. 15.
    Clayton, DF, George, JM 1999Synucleins in synaptic plasticity and neurodegenerative disordersJ Neurosci Res58120129CrossRefPubMedGoogle Scholar
  16. 16.
    Murphy, DD, Rueter, SM, Trojanowski, JQ, Lee, VM 2000Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neuronsJ Neurosci2032143220PubMedGoogle Scholar
  17. 17.
    George, JM, Jin, H, Woods, WS, Clayton, DF 1995Characterization of a novel protein regulated during the critical period for song learning in the zebra finchNeuron15361372CrossRefPubMedGoogle Scholar
  18. 18.
    Iwai, A, Masliah, E, Yoshimoto, M,  et al. 1995The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous systemNeuron14467475CrossRefPubMedGoogle Scholar
  19. 19.
    Bayer, TA, Jakala, P, Hartmann, T,  et al. 1999Neural expression profile of alpha-synuclein in developing human cortexNeuroreport1027992803CrossRefPubMedGoogle Scholar
  20. 20.
    Galvin, JE, Schuck, TM, Lee, VM, Trojanowski, JQ 2001Differential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigraExp Neurol168347355CrossRefPubMedGoogle Scholar
  21. 21.
    Hong, L, Ko, HW, Gwag, BJ,  et al. 1998The cDNA cloning and ontogeny of mouse alpha-synucleinNeuroreport912391243CrossRefPubMedGoogle Scholar
  22. 22.
    Hsu, LJ, Mallory, M, Xia, Y,  et al. 1998Expression pattern of synucleins (non-A beta component of Alzheimer’s disease amyloid precursor protein/alpha-synuclein) during murine brain developmentJ Neurochem71338344CrossRefPubMedGoogle Scholar
  23. 23.
    Petersen, K, Olesen, OF, Mikkelsen, JD 1999Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortexNeuroscience91651659CrossRefPubMedGoogle Scholar
  24. 24.
    Tiunova, AA, Anokhin, KV, Saha, AR,  et al. 2000Chicken synucleins: cloning and expression in the developing embryoMech Dev99195198CrossRefPubMedGoogle Scholar
  25. 25.
    Kepes, JJ, Collins, J 1999Choroid plexus epithelium (normal and neoplastic) expresses synaptophysin. A potentially useful aid in differentiating carcinoma of the choroid plexus from metastatic papillary carcinomasJ Neuropathol Exp Neurol58398401CrossRefPubMedGoogle Scholar
  26. 26.
    Ohta, M, Kitamoto, T, Iwaki, T, Ohgami, T, Fukui, M, Tateishi, J 1993Immunohistochemical distribution of amyloid precursor protein during normal rat developmentBrain Res Dev Brain Res75151161CrossRefPubMedGoogle Scholar
  27. 27.
    Abeliovich, A, Schmitz, Y, Farinas, I,  et al. 2000Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine systemNeuron25239252CrossRefPubMedGoogle Scholar
  28. 28.
    Sommer, B, Barbieri, S, Hofele, K,  et al. 2000Mouse models of alpha-synucleinopathy and Lewy pathologyExp Gerontol3513891403CrossRefPubMedGoogle Scholar
  29. 29.
    Kenessey, A, Yen, SH 1993The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filamentsBrain Res6294046CrossRefPubMedGoogle Scholar
  30. 30.
    Jenkins, SM, Johnson, GV 1997Phosphorylation of microtubule-associated protein tau on Ser 262 by an embryonic 100 kDa protein kinaseBrain Res767305313CrossRefPubMedGoogle Scholar

Copyright information

© Society for Pediatric Pathology 2004

Authors and Affiliations

  • Ravi Raghavan
    • 1
  • Loes de Kruijff
    • 1
  • Monique D. Sterrenburg
    • 1
  • Beverly B. Rogers
    • 3
  • Christa L. Hladik
    • 2
  • Charles L. WhiteIII
    • 1
    • 2
  1. 1.Neuropathology Laboratory, Department of PathologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Immunohistochemistry Laboratory, Department of PathologyUniversity of Texas Southwestern Medical CenterDallasUSA
  3. 3.Department of PathologyChildren’s Medical CenterDallasUSA

Personalised recommendations