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Expression and Subcellular Location of Alpha-Synuclein During Mouse-Embryonic Development

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Abstract

Alpha-synuclein (α-SYN) is one of the major components of intracellular fibrillary aggregates in the brains of a subset of neurodegenerative disorders. Although α-SYN expression has been found in developing mouse brain, a detailed distribution during mouse-embryonic development has not been made. Here we describe the expression pattern of α-SYN during the development of mice from E9.5 to P0 by immunohistochemistry (IHC). As a result, α-SYN was detected as early as E9.5. During the embryonic stages, α-SYN was dynamically expressed in several regions of the brain. In the neocortex, expression was detected in the marginal zone (MZ) in the early stages and was later condensed in the MZ and in the subplate (SP); in the cerebellum, expression was initially detected in the deep cerebellar nuclei (DCN) and was later condensed in the Purkinje cells. These spatio-temporal expression patterns matched the neuronal migratory pathways and the formation of the synapse connections. Additionally, α-SYN was detected in the sensory systems, including the nasal mucosa, the optic cup, the sensory ganglia, and their dominating nerve fibers. Furthermore, the nuclear location of α-SYN protein was found in developing neurons in the early stages, and later it was mostly found in the non-nuclear compartments. This finding was further confirmed by Western blot analysis. These results suggest that α-SYN may be involved not only in the migration of neurons and in the synaptogenesis of the central nervous system (CNS) but also in the establishment of the sensory systems. The nuclear location of α-SYN may hint at an important function in these events.

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References

  • Akil O, Weber CM, Park SN, Ninkina N, Buchman V, Lustig LR (2008) Localization of synucleins in the Mammalian cochlea. J Assoc Res Otolaryngol 9:452–463

    Article  CAS  PubMed  Google Scholar 

  • Alerte TN, Akinfolarin AA, Friedrich EE, Mader SA, Hong CS, Perez RG (2008) Alpha-synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: lessons from viral transduction of knockout mice. Neurosci Lett 435:24–29

    Article  CAS  PubMed  Google Scholar 

  • Azeredo da Silveira S, Schneider BL, Cifuentes-Diaz C, Sage D, Abbas-Terki T, Iwatsubo T, Unser M, Aebischer P (2009) Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson’s disease. Hum Mol Genet 18:872–887

    CAS  PubMed  Google Scholar 

  • Baptista MJ, O’Farrell C, Daya S, Ahmad R, Miller DW, Hardy J, Farrer MJ, Cookson MR (2003) Co-ordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines. J Neurochem 85:957–968

    CAS  PubMed  Google Scholar 

  • Bar I, Lambert de Rouvroit C, Goffinet AM (2000) The evolution of cortical development. An hypothesis based on the role of the Reelin signaling pathway. Trends Neurosci 23:633–638

    Article  CAS  PubMed  Google Scholar 

  • Blue ME, Parnavelas JG (1983) The formation and maturation of synapses in the visual cortex of the rat. II. Quantitative analysis. J Neurocytol 12:697–712

    Article  CAS  PubMed  Google Scholar 

  • Bodis-Wollner I (1990) Visual deficits related to dopamine deficiency in experimental animals and Parkinson’s disease patients. Trends Neurosci 13:296–302

    Article  CAS  PubMed  Google Scholar 

  • Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22:8797–8807

    CAS  PubMed  Google Scholar 

  • Clayton DF, George JM (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58:120–129

    Article  CAS  PubMed  Google Scholar 

  • Daly C, Ziff EB (1997) Post-transcriptional regulation of synaptic vesicle protein expression and the developmental control of synaptic vesicle formation. J Neurosci 17:2365–2375

    CAS  PubMed  Google Scholar 

  • Di Porzio U, Zuddas A, Cosenza-Murphy DB, Barker JL (1990) Early appearance of tyrosine hydroxylase immunoreactive cells in the mesencephalon of mouse embryos. Int J Dev Neurosci 8:523–532

    Article  CAS  PubMed  Google Scholar 

  • Djamgoz MB, Hankins MW, Hirano J, Archer SN (1997) Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Res 37:3509–3529

    Article  CAS  PubMed  Google Scholar 

  • Duda JE, Shah U, Arnold SE, Lee VM, Trojanowski JQ (1999) The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp Neurol 160:515–522

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164

    Article  CAS  PubMed  Google Scholar 

  • George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–372

    Article  CAS  PubMed  Google Scholar 

  • Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989

    Article  CAS  PubMed  Google Scholar 

  • Giasson BI, Duda JE, Forman MS, Lee VM, Trojanowski JQ (2001) Prominent perikaryal expression of alpha- and beta-synuclein in neurons of dorsal root ganglion and in medullary neurons. Exp Neurol 172:354–362

    Article  CAS  PubMed  Google Scholar 

  • Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42:8465–8471

    Article  CAS  PubMed  Google Scholar 

  • Hong L, Ko HW, Gwag BJ, Joe E, Lee S, Kim YT, Suh YH (1998) The cDNA cloning and ontogeny of mouse alpha-synuclein. Neuroreport 9:1239–1243

    CAS  PubMed  Google Scholar 

  • Hsu LJ, Mallory M, Xia Y, Veinbergs I, Hashimoto M, Yoshimoto M, Thal LJ, Saitoh T, Masliah E (1998) Expression 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

    Article  CAS  PubMed  Google Scholar 

  • Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T (1995) The 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

    Article  CAS  PubMed  Google Scholar 

  • Iwatsubo T (2003) Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 250(Suppl 3):III11–III14

    Google Scholar 

  • Jackson GR, Owsley C (2003) Visual dysfunction, neurodegenerative diseases, and aging. Neurol Clin N Am 21:709–728

    Google Scholar 

  • Jobst EE, Melnick ME, Byl NN, Dowling GA, Aminoff MJ (1997) Sensory perception in Parkinson disease. Arch Neurol 54:450–454

    CAS  PubMed  Google Scholar 

  • Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023

    Article  CAS  PubMed  Google Scholar 

  • Lee SS, Kim YM, Junn E, Lee G, Park KH, Tanaka M, Ronchetti RD, Quezado MM, Mouradian MM (2003) Cell cycle aberrations by alpha-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies. Neurobiol Aging 24:687–696

    Article  CAS  PubMed  Google Scholar 

  • Lotharius J, Brundin P (2002a) Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson’s disease. Hum Mol Genet 11:2395–2407

    Article  CAS  PubMed  Google Scholar 

  • Lotharius J, Brundin P (2002b) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942

    Article  CAS  PubMed  Google Scholar 

  • Lotharius J, Barg S, Wiekop P, Lundberg C, Raymon HK, Brundin P (2002) Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 277:38884–38894

    Article  CAS  PubMed  Google Scholar 

  • Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815

    CAS  PubMed  Google Scholar 

  • McLean PJ, Kawamata H, Ribich S, Hyman BT (2000) Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson’s disease-linked mutations. J Biol Chem 275:8812–8816

    Article  CAS  PubMed  Google Scholar 

  • Michell AW, Tofaris GK, Gossage H, Tyers P, Spillantini MG, Barker RA (2007) The effect of truncated human alpha-synuclein (1–120) on dopaminergic cells in a transgenic mouse model of Parkinson’s disease. Cell Transplant 16:461–474

    CAS  PubMed  Google Scholar 

  • Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K (2002) Immunohistochemical comparison of alpha- and beta-synuclein in adult rat central nervous system. Brain Res 941:118–126

    Article  CAS  PubMed  Google Scholar 

  • Murphy DD, Rueter SM, Trojanowski JQ, Lee VM (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20:3214–3220

    CAS  PubMed  Google Scholar 

  • Negro A, Brunati AM, Donella-Deana A, Massimino ML, Pinna LA (2002) Multiple phosphorylation of alpha-synuclein by protein tyrosine kinase Syk prevents eosin-induced aggregation. FASEB J 16:210–212

    CAS  PubMed  Google Scholar 

  • Payton JE, Perrin RJ, Woods WS, George JM (2004) Structural determinants of PLD2 inhibition by alpha-synuclein. J Mol Biol 337:1001–1009

    Article  CAS  PubMed  Google Scholar 

  • Peng X, Tehranian R, Dietrich P, Stefanis L, Perez RG (2005) Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J Cell Sci 118:3523–3530

    Article  CAS  PubMed  Google Scholar 

  • Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22:3090–3099

    CAS  PubMed  Google Scholar 

  • Perrone-Capano C, Di Porzio U (2000) Genetic and epigenetic control of midbrain dopaminergic neuron development. Int J Dev Biol 44:679–687

    CAS  PubMed  Google Scholar 

  • Petersen K, Olesen OF, Mikkelsen JD (1999) Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortex. Neuroscience 91:651–659

    Article  CAS  PubMed  Google Scholar 

  • Reyes S, Mitrofanis J (2008) Patterns of FOS expression in the spinal cord and periaqueductal grey matter of 6OHDA-lesioned rats. Int J Neurosci 118:1053–1079

    Article  CAS  PubMed  Google Scholar 

  • Schneider BL, Seehus CR, Capowski EE, Aebischer P, Zhang SC, Svendsen CN (2007) Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation. Hum Mol Genet 16:651–666

    Article  CAS  PubMed  Google Scholar 

  • Simon HH, Saueressig H, Wurst W, Goulding MD, O’Leary DD (2001) Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci 21:3126–3134

    CAS  PubMed  Google Scholar 

  • Smidt MP, Smits SM, Bouwmeester H, Hamers FP, van der Linden AJ, Hellemons AJ, Graw J, Burbach JP (2004) Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3. Development 131:1145–1155

    Article  CAS  PubMed  Google Scholar 

  • Specht CG, Tigaret CM, Rast GF, Thalhammer A, Rudhard Y, Schoepfer R (2005) Subcellular localisation of recombinant alpha- and gamma-synuclein. Mol Cell Neurosci 28:326–334

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473

    Article  CAS  PubMed  Google Scholar 

  • Surguchov A, Surgucheva I, Solessio E, Baehr W (1999) Synoretin—a new protein belonging to the synuclein family. Mol Cell Neurosci 13:95–103

    Article  CAS  PubMed  Google Scholar 

  • Tofaris GK, Spillantini MG (2007) Physiological and pathological properties of alpha-synuclein. Cell Mol Life Sci 64:2194–2201

    Article  CAS  PubMed  Google Scholar 

  • Trimarchi JM, Stadler MB, Roska B, Billings N, Sun B, Bartch B, Cepko CL (2007) Molecular heterogeneity of developing retinal ganglion and amacrine cells revealed through single cell gene expression profiling. J Comp Neurol 502:1047–1065

    Article  CAS  PubMed  Google Scholar 

  • Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S (2000) Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74:721–729

    Article  CAS  PubMed  Google Scholar 

  • Withers GS, George JM, Banker GA, Clayton DF (1997) Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res Dev Brain Res 99:87–94

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Zuo X, Li Y, Zhang C, Zhou M, Zhang YA, Ueda K, Chan P (2004) Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells. Neurosci Lett 367:34–39

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Ueda K, Chan P (2007) Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145:539–555

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (30572364) and Natural Science Foundation Project of CQ CSTC (2007BB5054)

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Authors and Affiliations

  1. Department of Histology and Embryology, Third Military Medical University, Shapingba District, Chongqing, 400038, China

    Shan-chuan Zhong, Xue Luo, Xing-shu Chen, Qi-yan Cai, Xing-hua Chen & Zhong-xiang Yao

  2. Department of Developmental Biology, Third Military Medical University, Shapingba District, Chongqing, 400038, China

    Shan-chuan Zhong, Xue Luo, Xing-shu Chen, Qi-yan Cai, Xing-hua Chen & Zhong-xiang Yao

  3. Physiotherapy and Rehabilitation Department of Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Jing Liu

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  1. Shan-chuan Zhong
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Correspondence to Zhong-xiang Yao.

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Zhong, Sc., Luo, X., Chen, Xs. et al. Expression and Subcellular Location of Alpha-Synuclein During Mouse-Embryonic Development. Cell Mol Neurobiol 30, 469–482 (2010). https://doi.org/10.1007/s10571-009-9473-4

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  • DOI: https://doi.org/10.1007/s10571-009-9473-4

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