Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Alpha-Synuclein Inclusion Formation in Human Oligodendrocytes

  • Yoon, Ye-Seul (Department of Anatomy, Konkuk University) ;
  • Ahn, Woo Jung (Department of Anatomy, Konkuk University) ;
  • Ricarte, Diadem (Department of Anatomy, Konkuk University) ;
  • Ortiz, Darlene (Department of Anatomy, Konkuk University) ;
  • Shin, Chan Young (Research Institute of Medical Science, Konkuk University) ;
  • Lee, Seung-Jae (Departments of Medicine and Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine) ;
  • Lee, He-Jin (Department of Anatomy, Konkuk University)
  • Received : 2020.05.06
  • Accepted : 2020.05.20
  • Published : 2021.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by presence of α-synuclein-positive inclusions in the cytoplasm of oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are considered an integral part of the pathogenesis of MSA, leading to demyelination and neuronal demise. What is most puzzling in the research fields of GCIs is the origin of α-synuclein aggregates in GCIs, since adult oligodendrocytes do not express high levels of α-synuclein. The most recent leading hypothesis is that GCIs form via transfer and accumulation of α-synuclein from neurons to oligodendrocytes. However, studies regarding this subject are limited due to the absence of proper human cell models, to demonstrate the entry and accumulation of neuronal α-synuclein in human oligodendrocytes. Here, we generated mature human oligodendrocytes that can take up neuronderived α-synuclein and form GCI-like inclusions. Mature human oligodendrocytes are derived from neural stem cells via "oligosphere" formation and then into oligodendrocytes, treating the cells with the proper differentiation factors at each step. In the final cell preparations, oligodendrocytes consist of the majority population, while some astrocytes and unidentified stem cell-like cells were present as well. When these cells were exposed to α-synuclein proteins secreted from neuron-like human neuroblastoma cells, oligodendrocytes developed perinuclear inclusion bodies with α-synuclein immunoreactivity, resembling GCIs, while the stem cell-like cells showed α-synuclein-positive, scattered puncta in the cytoplasm. In conclusion, we have established a human oligodendrocyte model for the study of GCI formation, and the characterization and use of this model might pave the way for understanding the pathogenesis of MSA.

Keywords

References

  1. Arima, K., Ueda, K., Sunohara, N., Arakawa, K., Hirai, S., Nakamura, M., Tonozuka-Uehara, H. and Kawai, M. (1998) NACP/alphasynuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol. (Berl.) 96, 439-444. https://doi.org/10.1007/s004010050917
  2. Asi, Y. T., Simpson, J. E., Heath, P. R., Wharton, S. B., Lees, A. J., Revesz, T., Houlden, H. and Holton, J. L. (2014) Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia 62, 964-970. https://doi.org/10.1002/glia.22653
  3. Benrud-Larson, L. M., Sandroni, P., Schrag, A. and Low, P. A. (2005) Depressive symptoms and life satisfaction in patients with multiple system atrophy. Mov. Disord. 20, 951-957. https://doi.org/10.1002/mds.20450
  4. Desplats, P., Lee, H. J., Bae, E. J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E. and Lee, S. J. (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl. Acad. Sci. U.S.A. 106, 13010-13015. https://doi.org/10.1073/pnas.0903691106
  5. Jecmenica-Lukic, M., Poewe, W., Tolosa, E. and Wenning, G. K. (2012) Premotor signs and symptoms of multiple system atrophy. Lancet Neurol. 11, 361-368. https://doi.org/10.1016/S1474-4422(12)70022-4
  6. Kahle, P. J., Neumann, M., Ozmen, L., Muller, V., Jacobsen, H., Spooren, W., Fuss, B., Mallon, B., Macklin, W. B., Fujiwara, H., Hasegawa, M., Iwatsubo, T., Kretzschmar, H. A. and Haass, C. (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep. 3, 583-588. https://doi.org/10.1093/embo-reports/kvf109
  7. Kim, C., Ho, D. H., Suk, J. E., You, S., Michael, S., Kang, J., Joong Lee, S., Masliah, E., Hwang, D., Lee, H. J. and Lee, S. J. (2013) Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562. https://doi.org/10.1038/ncomms2534
  8. Lee, H. J., Bae, E. J. and Lee, S. J. (2014) Extracellular alpha--synuclein-a novel and crucial factor in Lewy body diseases. Nat. Rev. Neurol. 10, 92-98. https://doi.org/10.1038/nrneurol.2013.275
  9. Lee, H. J., Khoshaghideh, F., Patel, S. and Lee, S. J. (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci. 24, 1888-1896. https://doi.org/10.1523/JNEUROSCI.3809-03.2004
  10. Lee, H. J., Patel, S. and Lee, S. J. (2005) Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J. Neurosci. 25, 6016-6024. https://doi.org/10.1523/JNEUROSCI.0692-05.2005
  11. Lee, H. J., Ricarte, D., Ortiz, D. and Lee, S. J. (2019) Models of multiple system atrophy. Exp. Mol. Med. 51, 139.
  12. Lee, H. J., Suk, J. E., Patrick, C., Bae, E. J., Cho, J. H., Rho, S., Hwang, D., Masliah, E. and Lee, S. J. (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J. Biol. Chem. 285, 9262-9272. https://doi.org/10.1074/jbc.M109.081125
  13. Miller, D. W., Johnson, J. M., Solano, S. M., Hollingsworth, Z. R., Standaert, D. G. and Young, A. B. (2005) Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J. Neural Transm. 112, 1613-1624. https://doi.org/10.1007/s00702-005-0378-1
  14. Ozawa, T., Okuizumi, K., Ikeuchi, T., Wakabayashi, K., Takahashi, H. and Tsuji, S. (2001) Analysis of the expression level of alpha-synuclein mRNA using postmortem brain samples from pathologically confirmed cases of multiple system atrophy. Acta Neuropathol. 102, 188-190. https://doi.org/10.1007/s004010100367
  15. Papp, M. I., Kahn, J. E. and Lantos, P. L. (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and ShyDrager syndrome). J. Neurol. Sci. 94, 79-100. https://doi.org/10.1016/0022-510X(89)90219-0
  16. Peng, C., Gathagan, R. J., Covell, D. J., Medellin, C., Stieber, A., Robinson, J. L., Zhang, B., Pitkin, R. M., Olufemi, M. F., Luk, K. C., Trojanowski, J. Q. and Lee, V. M. (2018) Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies. Nature 557, 558-563. https://doi.org/10.1038/s41586-018-0104-4
  17. Pukass, K. and Richter-Landsberg, C. (2014) Oxidative stress promotes uptake, accumulation, and oligomerization of extracellular alpha-synuclein in oligodendrocytes. J. Mol. Neurosci. 52, 339-352. https://doi.org/10.1007/s12031-013-0154-x
  18. Reyes, J. F., Rey, N. L., Bousset, L., Melki, R., Brundin, P. and Angot, E. (2014) Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 62, 387-398. https://doi.org/10.1002/glia.22611
  19. Shults, C. W., Rockenstein, E., Crews, L., Adame, A., Mante, M., Larrea, G., Hashimoto, M., Song, D., Iwatsubo, T., Tsuboi, K. and Masliah, E. (2005) Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J. Neurosci. 25, 10689-10699. https://doi.org/10.1523/JNEUROSCI.3527-05.2005
  20. Stefanova, N., Reindl, M., Neumann, M., Haass, C., Poewe, W., Kahle, P. J. and Wenning, G. K. (2005) Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am. J. Pathol. 166, 869-876. https://doi.org/10.1016/S0002-9440(10)62307-3
  21. Valera, E. and Masliah, E. (2018) The neuropathology of multiple system atrophy and its therapeutic implications. Auton. Neurosci. 211, 1-6. https://doi.org/10.1016/j.autneu.2017.11.002
  22. Yazawa, I., Giasson, B. I., Sasaki, R., Zhang, B., Joyce, S., Uryu, K., Trojanowski, J. Q. and Lee, V. M. (2005) Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45, 847-859. https://doi.org/10.1016/j.neuron.2005.01.032

Cited by

  1. The Role of Glial Mitochondria in α-Synuclein Toxicity vol.8, 2021, https://doi.org/10.3389/fcell.2020.548283
  2. Neurons and Glia Interplay in α-Synucleinopathies vol.22, pp.9, 2021, https://doi.org/10.3390/ijms22094994