Visualization of early oligomeric α-synuclein pathology and its impact on the dopaminergic system in the (Thy-1)-h[A30P]α-syn transgenic mouse model.
A30P
Parkinson's disease
alpha-synuclein
oligomers
pS129
proximity ligation assay
Journal
Journal of neuroscience research
ISSN: 1097-4547
Titre abrégé: J Neurosci Res
Pays: United States
ID NLM: 7600111
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
02
06
2021
received:
14
01
2021
accepted:
02
07
2021
pubmed:
23
7
2021
medline:
11
2
2022
entrez:
22
7
2021
Statut:
ppublish
Résumé
Aggregation of alpha-synuclein (α-syn) into Lewy bodies and Lewy neurites is a pathological hallmark in the Parkinson´s disease (PD) brain. The formation of α-syn oligomers is believed to be an early pathogenic event and the A30P mutation in the gene encoding α-syn, causing familial PD, has been shown to cause an accelerated oligomerization. Due to the problem of preserving antigen conformation on tissue surfaces, α-syn oligomers are difficult to detect ex vivo using conventional immunohistochemistry with oligomer-selective antibodies. Herein, we have instead employed the previously reported α-syn oligomer proximity ligation assay (ASO-PLA), along with a wide variety of biochemical assays, to discern the pathological progression of α-syn oligomers and their impact on the dopaminergic system in male and female (Thy-1)-h[A30P]α-syn transgenic (A30P-tg) mice. Our results reveal a previously undetected abundance of α-syn oligomers in midbrain of young mice, whereas phosphorylated (pS129) and proteinase k-resistant α-syn species were observed to a larger extent in aged mice. Although we did not detect loss of dopaminergic neurons in A30P-tg mice, a dysregulation in the monoaminergic system was recorded in older mice. Taken together, ASO-PLA should be a useful method for the detection of early changes in α-syn aggregation on brain tissue, from experimental mouse models in addition to post mortem PD cases.
Substances chimiques
SNCA protein, human
0
Thy-1 Antigens
0
alpha-Synuclein
0
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2525-2539Informations de copyright
© 2021 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.
Références
Anderson, J. P., Walker, D. E., Goldstein, J. M., de Laat, R., Banducci, K., Caccavello, R. J., Barbour, R., Huang, J., Kling, K., Lee, M., Diep, L., Keim, P. S., Shen, X., Chataway, T., Schlossmacher, M. G., Seubert, P., Schenk, D., Sinha, S., Gai, W. P., & Chilcote, T. J. (2006). Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. Journal of Biological Chemistry, 281(40), 29739-29752. https://doi.org/10.1074/jbc.M600933200
Colla, E., Jensen, P. H., Pletnikova, O., Troncoso, J. C., Glabe, C., & Lee, M. K. (2012). Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. Journal of Neuroscience, 32(10), 3301-3305. https://doi.org/10.1523/JNEUROSCI.5368-11.2012
Conway, K. A., Lee, S.-J., Rochet, J.-C., Ding, T. T., Williamson, R. E., & Lansbury, P. T. (2000). Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: Implications for pathogenesis and therapy. Proceedings of the National Academy of Sciences, 97(2), 571-576. https://doi.org/10.1073/pnas.97.2.571
Cyr, M., Calon, F., Morissette, M., & Di Paolo, T. (2002). Estrogenic modulation of brain activity: Implications for schizophrenia and Parkinson’s disease. Journal of Psychiatry and Neuroscience, 27, 12-27.
Donadio, V., Doppler, K., Incensi, A., Kuzkina, A., Janzen, A., Mayer, G., Volkmann, J., Rizzo, G., Antelmi, E., Plazzi, G., Sommer, C., Liguori, R., & Oertel, W. H. (2019). Abnormal α-synuclein deposits in skin nerves: Intra- and inter-laboratory reproducibility. European Journal of Neurology, 26, 1245-1251. https://doi.org/10.1111/ene.13939
Donadio, V., Incensi, A., El-Agnaf, O., Rizzo, G., Vaikath, N., Del Sorbo, F., Scaglione, C., Capellari, S., Elia, A., Stanzani Maserati, M., Pantieri, R., & Liguori, R. (2018). Skin α-synuclein deposits differ in clinical variants of synucleinopathy: An in vivo study. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-32588-8
Ekmark-Lewén, S., Lindström, V., Gumucio, A., Ihse, E., Behere, A., Kahle, P. J., Nordström, E., Eriksson, M., Erlandsson, A., Bergström, J., & Ingelsson, M. (2018). Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice. Brain and Behavior, 8, e00915. https://doi.org/10.1002/brb3.915
Fagerqvist, T., Lindström, V., Nordström, E., Lord, A., Tucker, S. M. E., Su, X., Sahlin, C., Kasrayan, A., Andersson, J., Welander, H., Näsström, T., Holmquist, M., Schell, H., Kahle, P. J., Kalimo, H., Möller, C., Gellerfors, P., Lannfelt, L., Bergström, J., & Ingelsson, M. (2013). Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation. Journal of Neurochemistry, 126, 131-144. https://doi.org/10.1111/jnc.12175
Fauser, M., Pan-Montojo, F., Richter, C., Kahle, P. J., Schwarz, S. C., Schwarz, J., Storch, A., & Hermann, A. (2021). Chronic-progressive dopaminergic deficiency does not induce midbrain neurogenesis. Cells, 10(4), 775. https://doi.org/10.3390/cells10040775
Fortin, D. L., Troyer, M. D., Nakamura, K., Kubo, S. I., Anthony, M. D., & Edwards, R. H. (2004). Lipid rafts mediate the synaptic localization of alpha-synuclein. Journal of Neuroscience, 24(30), 6715-6723. https://doi.org/10.1523/JNEUROSCI.1594-04.2004
Freichel, C., Neumann, M., Ballard, T., Müller, V., Woolley, M., Ozmen, L., Borroni, E., Kretzschmar, H. A., Haass, C., Spooren, W., & Kahle, P. J. (2007). Age-dependent cognitive decline and amygdala pathology in α-synuclein transgenic mice. Neurobiology of Aging, 28(9), 1421-1435. https://doi.org/10.1016/j.neurobiolaging.2006.06.013
Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., & Iwatsubo, T. (2002). α-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biology, 4, 160-164. https://doi.org/10.1038/ncb748
Hoffmann, A.-C., Minakaki, G., Menges, S., Salvi, R., Savitskiy, S., Kazman, A., Vicente Miranda, H., Mielenz, D., Klucken, J., Winkler, J., & Xiang, W. (2019). Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-018-35811-8
Hughes, C. D., Choi, M. L., Ryten, M., Hopkins, L., Drews, A., Botía, J. A., Iljina, M., Rodrigues, M., Gagliano, S. A., Gandhi, S., Bryant, C., & Klenerman, D. (2019). Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis. Acta Neuropathologica, 137(1), 103-120. https://doi.org/10.1007/s00401-018-1907-y
Ingelsson, M. (2016). Alpha-synuclein oligomers-neurotoxic molecules in Parkinson’s disease and other Lewy body disorders. Frontiers in Neuroscience, 10. https://doi.org/10.3389/fnins.2016.00408
Keane, P. C., Hanson, P. S., Patterson, L., Blain, P. G., Hepplewhite, P., Khundakar, A. A., Judge, S. J., Kahle, P. J., LeBeau, F. E. N., & Morris, C. M. (2019). Trichloroethylene and its metabolite TaClo lead to degeneration of substantia nigra dopaminergic neurones: Effects in wild type and human A30P mutant α-synuclein mice. Neuroscience Letters, 711, 134437. https://doi.org/10.1016/j.neulet.2019.134437
Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schols, L., & Riess, O. (1998). AlaSOPro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nature Genetics, 18(2), 106-108. https://doi.org/10.1038/ng0298-106
Kumar, S. T., Jagannath, S., Francois, C., Vanderstichele, H., Stoops, E., & Lashuel, H. A. (2020). How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology. Neurobiology of Diseases, 146, 105086. https://doi.org/10.1016/j.nbd.2020.105086
Lashuel, H. A., Petre, B. M., Wall, J., Simon, M., Nowak, R. J., Walz, T., & Lansbury, P. T. (2002). α-Synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. Journal of Molecular Biology, 322(5), 1089-1102. https://doi.org/10.1016/S0022-2836(02)00735-0
Lassen, L. B., Gregersen, E., Isager, A. K., Betzer, C., Kofoed, R. H., & Jensen, P. H. (2018). ELISA method to detect α-synuclein oligomers in cell and animal models. PLoS ONE, 13, e0196056. https://doi.org/10.1371/journal.pone.0196056
Lindström, V., Fagerqvist, T., Nordström, E., Eriksson, F., Lord, A., Tucker, S., Andersson, J., Johannesson, M., Schell, H., Kahle, P. J., Möller, C., Gellerfors, P., Bergström, J., Lannfelt, L., & Ingelsson, M. (2014). Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice. Neurobiology of Diseases, 69, 134-143. https://doi.org/10.1016/j.nbd.2014.05.009
Luth, E. S., Stavrovskaya, I. G., Bartels, T., Kristal, B. S., & Selkoe, D. J. (2014). Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. Journal of Biological Chemistry, 289(31), 21490-21507. https://doi.org/10.1074/jbc.M113.545749
Marxreiter, F., Nuber, S., Kandasamy, M., Klucken, J., Aigner, R., Burgmayer, R., Couillard-Despres, S., Riess, O., Winkler, J., & Winner, B. (2009). Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein. European Journal of Neuroscience, 29, 879-890. https://doi.org/10.1111/j.1460-9568.2009.06641.x
Mosharov, E. V., Staal, R. G. W., Bové, J., Prou, D., Hananiya, A., Markov, D., Poulsen, N., Larsen, K. E., Moore, C. M. H., Troyer, M. D., Edwards, R. H., Przedborski, S., & Sulzer, D. (2006). α-Synuclein overexpression increases cytosolic catecholamine concentration. Journal of Neuroscience, 26(36), 9304-9311. https://doi.org/10.1523/JNEUROSCI.0519-06.2006
Näsström, T., Fagerqvist, T., Barbu, M., Karlsson, M., Nikolajeff, F., Kasrayan, A., Ekberg, M., Lannfelt, L., Ingelsson, M., & Bergström, J. (2011). The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of α-synuclein oligomers with distinct biochemical, morphological, and functional properties. Free Radical Biology and Medicine, 50, 428-437. https://doi.org/10.1016/j.freeradbiomed.2010.11.027
Nemani, V. M., Lu, W., Berge, V., Nakamura, K., Onoa, B., Lee, M. K., Chaudhry, F. A., Nicoll, R. A., & Edwards, R. H. (2010). Increased expression of α-Synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron, 65, 66-79. https://doi.org/10.1016/j.neuron.2009.12.023
Neumann, M., Kahle, P. J., Giasson, B. I., Ozmen, L., Borroni, E., Spooren, W., Müller, V., Odoy, S., Fujiwara, H., Hasegawa, M., Iwatsubo, T., Trojanowski, J. Q., Kretzschmar, H. A., & Haass, C. (2002). Misfolded proteinase K-resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies. Journal of Clinical Investigation, 110(10), 1429-1439. https://doi.org/10.1172/jci200215777
Neumann, M., Müller, V., Kretzschmar, H. A., Haass, C., & Kahle, P. J. (2004). Regional distribution of proteinase K-resistant α-synuclein correlates with Lewy body disease stage. Journal of Neuropathology & Experimental Neurology, 63(12), 1225-1235. https://doi.org/10.1093/jnen/63.12.1225
Neuner, J., Filser, S., Michalakis, S., Biel, M., & Herms, J. (2015). A30P α-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network. Scientific Reports, 4(1). https://doi.org/10.1038/srep03931
Okochi, M., Walter, J., Koyama, A., Nakajo, S., Baba, M., Iwatsubo, T., Meijer, L., Kahle, P. J., & Haass, C. (2000). Constitutive phosphorylation of the Parkinson’s disease associated α-synuclein. Journal of Biological Chemistry, 275(1), 390-397. https://doi.org/10.1074/jbc.275.1.390
Outeiro, T. F., Putcha, P., Tetzlaff, J. E., Spoelgen, R., Koker, M., Carvalho, F., Hyman, B. T., & McLean, P. J. (2008). Formation of toxic oligomeric α-synuclein species in living cells. PLoS ONE, 3(4), e1867. https://doi.org/10.1371/journal.pone.0001867
Øverli, Ø., Harris, C. A., & Winberg, S. (1999). Short-term effects of fights for social dominance and the establishment of dominant-subordinate relationships on brain monoamines and cortisol in rainbow trout. Brain, Behavior and Evolution, 54, 263-275. https://doi.org/10.1159/000006627
Rathke-Hartlieb, S., Kahle, P. J., Neumann, M., Ozmen, L., Haid, S., Okochi, M., Haass, C., & Schulz, J. B. (2001). Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant α-synuclein transgenic mice. Journal of Neurochemistry, 77(4), 1181-1184. https://doi.org/10.1046/j.1471-4159.2001.00366.x
Roberts, R. F., Bengoa-Vergniory, N., & Alegre-Abarrategui, J. (2019). Alpha-synuclein proximity ligation assay (AS-PLA) in brain sections to probe for alpha-synuclein oligomers. In T. Bartels (Ed.), Alpha-synuclein: Methods and protocols (pp. 69-76). Springer.
Roberts, R. F., Wade-Martins, R., & Alegre-Abarrategui, J. (2015). Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson’s disease brain. Brain, 138, 1642-1657. https://doi.org/10.1093/brain/awv040
Rockenstein, E., Nuber, S., Overk, C. R., Ubhi, K., Mante, M., Patrick, C., Adame, A., Trejo-Morales, M., Gerez, J., Picotti, P., Jensen, P. H., Campioni, S., Riek, R., Winkler, J., Gage, F. H., Winner, B., & Masliah, E. (2014). Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain, 137, 1496-1513. https://doi.org/10.1093/brain/awu057
Samuel, F., Flavin, W. P., Iqbal, S., Pacelli, C., Sri Renganathan, S. D., Trudeau, L. E., Campbell, E. M., Fraser, P. E., & Tandon, A. (2016). Effects of serine 129 phosphorylation on α-synuclein aggregation, membrane association, and internalization. Journal of Biological Chemistry, 291, 4374-4385. https://doi.org/10.1074/jbc.M115.705095
Schell, H., Hasegawa, T., Neumann, M., & Kahle, P. J. (2009). Nuclear and neuritic distribution of serine-129 phosphorylated α-synuclein in transgenic mice. Neuroscience, 160(4), 796-804. https://doi.org/10.1016/j.neuroscience.2009.03.002
Sekiya, H., Kowa, H., Koga, H., Takata, M., Satake, W., Futamura, N., Funakawa, I., Jinnai, K., Takahashi, M., Kondo, T., Ueno, Y., Kanagawa, M., Kobayashi, K., & Toda, T. (2019). Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation. Acta Neuropathologica, 137, 455-466. https://doi.org/10.1007/s00401-019-01961-w
Shannon, N. J., Gunnet, J. W., & Moore, K. E. (2006). A comparison of biochemical indices of 5-hydroxytryptaminergic neuronal activity following electrical stimulation of the dorsal raphe nucleus. Journal of Neurochemistry, 47(3), 958-965. https://doi.org/10.1111/j.1471-4159.1986.tb00704.x
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997). α-Synuclein in Lewy bodies. Nature, 388(6645), 839-840. https://doi.org/10.1038/42166
Taylor, T. N., Potgieter, D., Anwar, S., Senior, S. L., Janezic, S., Threlfell, S., Ryan, B., Parkkinen, L., Deltheil, T., Cioroch, M., Livieratos, A., Oliver, P. L., Jennings, K. A., Davies, K. E., Ansorge, O., Bannerman, D. M., Cragg, S. J., & Wade-Martins, R. (2014). Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse. Neurobiology of Diseases, 62, 193-207. https://doi.org/10.1016/j.nbd.2013.10.005
Zhang, J., Li, X., & Li, J.-D. (2019). The roles of post-translational modifications on α-synuclein in the pathogenesis of Parkinson’s diseases. Frontiers in Neuroscience, 13. https://doi.org/10.3389/fnins.2019.00381