Skip to main content

Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models

Acta Neuropathologica volume 138, pages 415–441 (2019)Cite this article

A Correction to this article was published on 03 September 2019

This article has been updated

Abstract

Multiple system atrophy (MSA) is characterized by the presence of distinctive glial cytoplasmic inclusions (GCIs) within oligodendrocytes that contain the neuronal protein alpha-synuclein (aSyn) and the oligodendroglia-specific phosphoprotein TPPP/p25α. However, the role of oligodendroglial aSyn and p25α in the formation of aSyn-rich GCIs remains unclear. To address this conundrum, we have applied human aSyn (haSyn) pre-formed fibrils (PFFs) to rat wild-type (WT)-, haSyn-, or p25α-overexpressing oligodendroglial cells and to primary differentiated oligodendrocytes derived from WT, knockout (KO)-aSyn, and PLP-haSyn-transgenic mice. HaSyn PFFs are readily taken up by oligodendroglial cells and can recruit minute amounts of endogenous aSyn into the formation of insoluble, highly aggregated, pathological assemblies. The overexpression of haSyn or p25α accelerates the recruitment of endogenous protein and the generation of such aberrant species. In haSyn PFF-treated primary oligodendrocytes, the microtubule and myelin networks are disrupted, thus recapitulating a pathological hallmark of MSA, in a manner totally dependent upon the seeding of endogenous aSyn. Furthermore, using oligodendroglial and primary cortical cultures, we demonstrated that pathology-related S129 aSyn phosphorylation depends on aSyn and p25α protein load and may involve different aSyn “strains” present in oligodendroglial and neuronal synucleinopathies. Importantly, this hypothesis was further supported by data obtained from human post-mortem brain material derived from patients with MSA and dementia with Lewy bodies. Finally, delivery of haSyn PFFs into the mouse brain led to the formation of aberrant aSyn forms, including the endogenous protein, within oligodendroglia and evoked myelin decompaction in WT mice, but not in KO-aSyn mice. This line of research highlights the role of endogenous aSyn and p25α in the formation of pathological aSyn assemblies in oligodendrocytes and provides in vivo evidence of the contribution of oligodendroglial aSyn in the establishment of aSyn pathology in MSA.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Change history

  • 03 September 2019

    he original version of this article

References

  1. Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K (1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA 91:5562–5566

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Angot E, Steiner JA, Lema Tome CM, Ekstrom P, Mattsson B, Bjorklund A et al (2012) Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 7:e39465. https://doi.org/10.1371/journal.pone.0039465

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T et al (2014) Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia 62:964–970. https://doi.org/10.1002/glia.22653

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bernis ME, Babila JT, Breid S, Wusten KA, Wullner U, Tamguney G (2015) Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein. Acta Neuropathol Commun 3:75. https://doi.org/10.1186/s40478-015-0254-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Bottenstein JE, Sato GH (1979) Growth of a rat neuroblastoma cell line in serum-free supplemented medium. Proc Natl Acad Sci USA 76:514–517

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Cho MK, Nodet G, Kim HY, Jensen MR, Bernado P, Fernandez CO et al (2009) Structural characterization of alpha-synuclein in an aggregation prone state. Protein Sci 18:1840–1846. https://doi.org/10.1002/pro.194

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Cruz-Martinez P, Gonzalez-Granero S, Molina-Navarro MM, Pacheco-Torres J, Garcia-Verdugo JM, Geijo-Barrientos E et al (2016) Intraventricular injections of mesenchymal stem cells activate endogenous functional remyelination in a chronic demyelinating murine model. Cell Death Dis 7:e2223. https://doi.org/10.1038/cddis.2016.130

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Dickson DW, Liu W, Hardy J, Farrer M, Mehta N, Uitti R et al (1999) Widespread alterations of alpha-synuclein in multiple system atrophy. Am J Pathol 155:1241–1251

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Djelloul M, Holmqvist S, Boza-Serrano A, Azevedo C, Yeung MS, Goldwurm S et al (2015) Alpha-synuclein expression in the oligodendrocyte lineage: an in vitro and in vivo study using rodent and human models. Stem Cell Reports 5:174–184. https://doi.org/10.1016/j.stemcr.2015.07.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Don AS, Hsiao JH, Bleasel JM, Couttas TA, Halliday GM, Kim WS (2014) Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun 2:150. https://doi.org/10.1186/s40478-014-0150-6

    Article  PubMed  PubMed Central  Google Scholar 

  11. Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I et al (2000) Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol 59:830–841

    CAS  Article  PubMed  Google Scholar 

  12. Ettle B, Kerman BE, Valera E, Gillmann C, Schlachetzki JC, Reiprich S et al (2016) Alpha-synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. Acta Neuropathol 132:59–75. https://doi.org/10.1007/s00401-016-1572-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Ettle B, Reiprich S, Deusser J, Schlachetzki JC, Xiang W, Prots I et al (2014) Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells. Mol Cell Neurosci 62:68–78. https://doi.org/10.1016/j.mcn.2014.06.012

    CAS  Article  PubMed  Google Scholar 

  14. Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372:249–263. https://doi.org/10.1056/NEJMra1311488

    CAS  Article  PubMed  Google Scholar 

  15. Grigoletto J, Pukass K, Gamliel A, Davidi D, Katz-Brull R, Richter-Landsberg C et al (2017) Higher levels of myelin phospholipids in brains of neuronal alpha-synuclein transgenic mice precede myelin loss. Acta Neuropathol Commun 5:37. https://doi.org/10.1186/s40478-017-0439-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Gustke N, Steiner B, Mandelkow EM, Biernat J, Meyer HE, Goedert M et al (1992) The Alzheimer-like phosphorylation of tau protein reduces microtubule binding and involves Ser-Pro and Thr-Pro motifs. FEBS Lett 307:199–205

    CAS  Article  PubMed  Google Scholar 

  17. Jellinger KA (2018) Multiple system atrophy: an oligodendroglioneural synucleinopathy1. J Alzheimers Dis 62:1141–1179. https://doi.org/10.3233/JAD-170397

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Jellinger KA (2006) P25alpha immunoreactivity in multiple system atrophy and Parkinson disease. Acta Neuropathol 112:112. https://doi.org/10.1007/s00401-006-0075-7

    Article  PubMed  Google Scholar 

  19. Jin H, Ishikawa K, Tsunemi T, Ishiguro T, Amino T, Mizusawa H (2008) Analyses of copy number and mRNA expression level of the alpha-synuclein gene in multiple system atrophy. J Med Dent Sci 55:145–153

    PubMed  Google Scholar 

  20. Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W et al (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3:583–588. https://doi.org/10.1093/embo-reports/kvf109

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Kaji S, Maki T, Kinoshita H, Uemura N, Ayaki T, Kawamoto Y et al (2018) Pathological endogenous alpha-synuclein accumulation in oligodendrocyte precursor cells potentially induces inclusions in multiple system atrophy. Stem Cell Rep 10:356–365. https://doi.org/10.1016/j.stemcr.2017.12.001

    CAS  Article  Google Scholar 

  22. Kim HY, Cho MK, Kumar A, Maier E, Siebenhaar C, Becker S et al (2009) Structural properties of pore-forming oligomers of alpha-synuclein. J Am Chem Soc 131:17482–17489. https://doi.org/10.1021/ja9077599

    CAS  Article  PubMed  Google Scholar 

  23. Kisos H, Pukass K, Ben-Hur T, Richter-Landsberg C, Sharon R (2012) Increased neuronal alpha-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling alpha-synucleinopathies. PLoS One 7:e46817. https://doi.org/10.1371/journal.pone.0046817

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Konno M, Hasegawa T, Baba T, Miura E, Sugeno N, Kikuchi A et al (2012) Suppression of dynamin GTPase decreases alpha-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy. Mol Neurodegener 7:38. https://doi.org/10.1186/1750-1326-7-38

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Kovacs GG, Laszlo L, Kovacs J, Jensen PH, Lindersson E, Botond G, Molnar T et al (2004) Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies. Neurobiol Dis 17:155–162. https://doi.org/10.1016/j.nbd.2004.06.006

    CAS  Article  PubMed  Google Scholar 

  26. Kragh CL, Lund LB, Febbraro F, Hansen HD, Gai WP, El-Agnaf O et al (2009) Alpha-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells. J Biol Chem 284:10211–10222. https://doi.org/10.1074/jbc.M809671200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Lassen LB, Gregersen E, Isager AK, Betzer C, Kofoed RH, Jensen PH (2018) ELISA method to detect alpha-synuclein oligomers in cell and animal models. PLoS One 13:e0196056. https://doi.org/10.1371/journal.pone.0196056

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Lindersson E, Lundvig D, Petersen C, Madsen P, Nyengaard JR, Hojrup P et al (2005) p25alpha Stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies. J Biol Chem 280:5703–5715. https://doi.org/10.1074/jbc.M410409200

    CAS  Article  PubMed  Google Scholar 

  29. Luk KC, Song C, O’Brien P, Stieber A, Branch JR, Brunden KR et al (2009) Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci USA 106:20051–20056. https://doi.org/10.1073/pnas.0908005106

    Article  PubMed  PubMed Central  Google Scholar 

  30. Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H et al (2013) Prion-like spreading of pathological alpha-synuclein in brain. Brain 136:1128–1138. https://doi.org/10.1093/brain/awt037

    Article  PubMed  PubMed Central  Google Scholar 

  31. Matsuo A, Akiguchi I, Lee GC, McGeer EG, McGeer PL, Kimura J (1998) Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol 153:735–744. https://doi.org/10.1016/S0002-9440(10)65617-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85:890–902

    CAS  Article  PubMed  Google Scholar 

  33. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872. https://doi.org/10.1212/01.wnl.0000187889.17253.b1

    CAS  Article  PubMed  Google Scholar 

  34. Melki R (2015) Role of different alpha-synuclein strains in synucleinopathies, similarities with other neurodegenerative diseases. J Parkinsons Dis 5:217–227. https://doi.org/10.3233/JPD-150543

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Miller DW, Johnson JM, Solano SM, Hollingsworth ZR, Standaert DG, Young AB (2005) Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J Neural Transm (Vienna) 112:1613–1624. https://doi.org/10.1007/s00702-005-0378-1

    CAS  Article  Google Scholar 

  36. Mondragon-Rodriguez S, Perry G, Luna-Munoz J, Acevedo-Aquino MC, Williams S (2014) Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer’s disease and Down syndrome. Neuropathol Appl Neurobiol 40:121–135. https://doi.org/10.1111/nan.12084

    CAS  Article  PubMed  Google Scholar 

  37. Ota K, Obayashi M, Ozaki K, Ichinose S, Kakita A, Tada M et al (2014) Relocation of p25alpha/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy. Acta Neuropathol Commun 2:136. https://doi.org/10.1186/s40478-014-0136-4

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ozawa T, Okuizumi K, Ikeuchi T, Wakabayashi K, Takahashi H, 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

    CAS  PubMed  Google Scholar 

  39. Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100

    CAS  Article  PubMed  Google Scholar 

  40. Papp MI, Lantos PL (1992) Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy. J Neurol Sci 107:172–182

    CAS  Article  PubMed  Google Scholar 

  41. Papp MI, Lantos PL (1994) The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 117(Pt 2):235–243

    Article  PubMed  Google Scholar 

  42. Paumier KL, Luk KC, Manfredsson FP, Kanaan NM, Lipton JW, Collier TJ et al (2015) Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers alpha-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185–199. https://doi.org/10.1016/j.nbd.2015.06.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Payne SC, Bartlett CA, Harvey AR, Dunlop SA, Fitzgerald M (2012) Myelin sheath decompaction, axon swelling, and functional loss during chronic secondary degeneration in rat optic nerve. Invest Ophthalmol Vis Sci 53:6093–6101. https://doi.org/10.1167/iovs.12-10080

    CAS  Article  PubMed  Google Scholar 

  44. Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M et al (2015) Alpha-synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344. https://doi.org/10.1038/nature14547

    CAS  Article  PubMed  Google Scholar 

  45. Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A, Robinson JL et al (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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Polinski NK, Volpicelli-Daley LA, Sortwell CE, Luk KC, Cremades N, Gottler LM et al (2018) Best practices for generating and using alpha-synuclein pre-formed fibrils to model Parkinson’s disease in rodents. J Parkinsons Dis 8:303–322. https://doi.org/10.3233/JPD-171248

    Article  PubMed  PubMed Central  Google Scholar 

  47. Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB et al (2015) Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 112:E5308–E5317. https://doi.org/10.1073/pnas.1514475112

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Pukass K, Goldbaum O, Richter-Landsberg C (2015) Mitochondrial impairment and oxidative stress compromise autophagosomal degradation of alpha-synuclein in oligodendroglial cells. J Neurochem 135:194–205. https://doi.org/10.1111/jnc.13256

    CAS  Article  PubMed  Google Scholar 

  49. Pukass K, 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

    CAS  Article  PubMed  Google Scholar 

  50. Radford R, Rcom-H’cheo-Gauthier A, Wong MB, Eaton ED, Quilty M, Blizzard C et al (2015) The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to alpha-synuclein inclusions. Mol Cell Neurosci 65:68–81. https://doi.org/10.1016/j.mcn.2015.02.015

    CAS  Article  PubMed  Google Scholar 

  51. Reimer L, Vesterager LB, Betzer C, Zheng J, Nielsen LD, Kofoed RH et al (2018) Inflammation kinase PKR phosphorylates alpha-synuclein and causes alpha-synuclein-dependent cell death. Neurobiol Dis 115:17–28. https://doi.org/10.1016/j.nbd.2018.03.001

    CAS  Article  PubMed  Google Scholar 

  52. Rey NL, George S, Steiner JA, Madaj Z, Luk KC, Trojanowski JQ et al (2018) Spread of aggregates after olfactory bulb injection of alpha-synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathol 135:65–83. https://doi.org/10.1007/s00401-017-1792-9

    CAS  Article  PubMed  Google Scholar 

  53. Rey NL, Petit GH, Bousset L, Melki R, Brundin P (2013) Transfer of human alpha-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol 126:555–573. https://doi.org/10.1007/s00401-013-1160-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ et al (2016) Widespread transneuronal propagation of alpha-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med 213:1759–1778. https://doi.org/10.1084/jem.20160368

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E (2014) Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 62:387–398. https://doi.org/10.1002/glia.22611

    Article  PubMed  Google Scholar 

  56. Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM (2000) alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14. https://doi.org/10.1002/1097-4547(20001001)62:1%3c9:AID-JNR2%3e3.0.CO;2-U

    CAS  Article  PubMed  Google Scholar 

  57. Richter-Landsberg C, Heinrich M (1996) OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. J Neurosci Res 45:161–173. https://doi.org/10.1002/(SICI)1097-4547(19960715)45:2%3c161:AID-JNR8%3e3.0.CO;2-8

    CAS  Article  PubMed  Google Scholar 

  58. Rockenstein E, Ubhi K, Inglis C, Mante M, Patrick C, Adame A et al (2012) Neuronal to oligodendroglial alpha-synuclein redistribution in a double transgenic model of multiple system atrophy. NeuroReport 23:259–264. https://doi.org/10.1097/WNR.0b013e3283509842

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Sacino AN, Thomas MA, Ceballos-Diaz C, Cruz PE, Rosario AM, Lewis J et al (2013) Conformational templating of alpha-synuclein aggregates in neuronal-glial cultures. Mol Neurodegener 8:17. https://doi.org/10.1186/1750-1326-8-17

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Solano SM, Miller DW, Augood SJ, Young AB, Penney JB Jr (2000) Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson’s disease. Ann Neurol 47:201–210

    CAS  Article  PubMed  Google Scholar 

  61. Song YJ, Lundvig DM, Huang Y, Gai WP, Blumbergs PC, Hojrup P et al (2007) p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171:1291–1303. https://doi.org/10.2353/ajpath.2007.070201

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208

    CAS  Article  PubMed  Google Scholar 

  63. Sun Q, Gamblin TC (2009) Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization. Biochemistry 48:6002–6011. https://doi.org/10.1021/bi900602h

    CAS  Article  PubMed  Google Scholar 

  64. Takeda A, Arai N, Komori T, Iseki E, Kato S, Oda M (1997) Tau immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 234:63–66

    CAS  Article  PubMed  Google Scholar 

  65. Tirian L, Hlavanda E, Olah J, Horvath I, Orosz F, Szabo B et al (2003) TPPP/p25 promotes tubulin assemblies and blocks mitotic spindle formation. Proc Natl Acad Sci USA 100:13976–13981. https://doi.org/10.1073/pnas.2436331100

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Trojanowski JQ, Revesz T (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33:615–620. https://doi.org/10.1111/j.1365-2990.2007.00907.x

    CAS  Article  PubMed  Google Scholar 

  67. Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44:415–422. https://doi.org/10.1002/ana.410440324

    CAS  Article  PubMed  Google Scholar 

  68. Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O, Norris EH et al (2006) Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol 168:947–961

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Vekrellis K, Xilouri M, Emmanouilidou E, Stefanis L (2009) Inducible over-expression of wild type alpha-synuclein in human neuronal cells leads to caspase-dependent non-apoptotic death. J Neurochem 109:1348–1362. https://doi.org/10.1111/j.1471-4159.2009.06054.x

    CAS  Article  PubMed  Google Scholar 

  70. Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283:23542–23556. https://doi.org/10.1074/jbc.M801992200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Volpicelli-Daley LA, Luk KC, Lee VM (2014) Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat Protoc 9:2135–2146. https://doi.org/10.1038/nprot.2014.143

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A et al (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71. https://doi.org/10.1016/j.neuron.2011.08.033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182

    CAS  Article  PubMed  Google Scholar 

  74. Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246. https://doi.org/10.1002/ana.21465

    CAS  Article  PubMed  Google Scholar 

  75. Woerman AL, Kazmi SA, Patel S, Freyman Y, Oehler A, Aoyagi A et al (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49–63. https://doi.org/10.1007/s00401-017-1762-2

    CAS  Article  PubMed  Google Scholar 

  76. Woerman AL, Watts JC, Aoyagi A, Giles K, Middleton LT, Prusiner SB (2018) Alpha-synuclein: multiple system atrophy prions. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a024588

    Article  PubMed  PubMed Central  Google Scholar 

  77. Wong JH, Halliday GM, Kim WS (2014) Exploring myelin dysfunction in multiple system atrophy. Exp Neurobiol 23:337–344. https://doi.org/10.5607/en.2014.23.4.337

    Article  PubMed  PubMed Central  Google Scholar 

  78. Xilouri M, Brekk OR, Landeck N, Pitychoutis PM, Papasilekas T, Papadopoulou-Daifoti Z et al (2013) Boosting chaperone-mediated autophagy in vivo mitigates alpha-synuclein-induced neurodegeneration. Brain 136:2130–2146. https://doi.org/10.1093/brain/awt131

    Article  PubMed  Google Scholar 

  79. Xilouri M, Kyratzi E, Pitychoutis PM, Papadopoulou-Daifoti Z, Perier C, Vila M et al (2012) Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system. Hum Mol Genet 21:874–889. https://doi.org/10.1093/hmg/ddr521

    CAS  Article  PubMed  Google Scholar 

  80. Xiong B, Li A, Lou Y, Chen S, Long B, Peng J et al (2017) Precise cerebral vascular atlas in stereotaxic coordinates of whole mouse brain. Front Neuroanat 11:128. https://doi.org/10.3389/fnana.2017.00128

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the BRFAA biological imaging facility for their valuable contribution to confocal imaging and image analysis, George Tzanoukos (M.Sc., Head of the Biomedical Engineering Department, BRFAA) for technical assistance, and the BRFAA Animal Facility. The authors would also like to thank Dr. Nadia Stefanova (Innsbruck University) for providing the C57BL6 PLP-haSyn transgenic mice and Imago Pharmaceuticals for providing the 11A5 antibody. The authors also like to thank Dr. Lee Clough for editing the manuscript. PHJ was supported by the Lundbeck foundation Grant R223-2015-4222 and R248-2016-25. This work was supported by an MSA Coalition grant and a Bodossaki Grant to MX. Partial support was provided by an NIH grant NS1000876 to BG and by the Innovative Medicines Initiative 2 Joint Undertaking under Grant agreement No. 116060 (IMPRiND) to LS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. This work was supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038. The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.

Author information

Authors and Affiliations

  1. Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, 11527, Athens, Greece

    Panagiota Mavroeidi, Fedra Arvanitaki, Anastasia-Kiriaki Karakitsou, Maria Vetsi, Leonidas Stefanis & Maria Xilouri

  2. Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

    Ismini Kloukina

  3. German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany

    Markus Zweckstetter

  4. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany

    Markus Zweckstetter, Karin Giller & Stefan Becker

  5. Department of Neuroscience, University of Florida, Gainesville, FL, 32610, USA

    Zachary A. Sorrentino & Benoit I. Giasson

  6. Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA

    Zachary A. Sorrentino & Benoit I. Giasson

  7. McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA

    Benoit I. Giasson

  8. DANDRITE-Danish Research Institute of Translational Neuroscience and Department of Biomedicine, University of Aarhus, Aarhus C, Denmark

    Poul Henning Jensen

  9. 1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Leonidas Stefanis

Authors
  1. Panagiota Mavroeidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fedra Arvanitaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anastasia-Kiriaki Karakitsou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Vetsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ismini Kloukina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markus Zweckstetter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karin Giller
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stefan Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zachary A. Sorrentino
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Benoit I. Giasson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Poul Henning Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Leonidas Stefanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maria Xilouri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PM carried out the experiments, analyzed and interpreted the data, generated the figures, and participated in the study design, and in writing the manuscript. FA carried out the immunohistochemical analysis of the hPFF-injected mouse brains. AKK performed the initial experiments with the uptake of hPFFs in the OLN cell lines. MV carried out additional experiments required for resubmission. IK performed the EM analysis. MZ, KG, and SB generated the haSyn PFFs. ZS and BG performed immunohistochemical staining and comparative analyses of human brain tissue. PHJ provided the OLN cells, p25α plasmid, and p25α antibody. LS participated in study design, data interpretation, and in writing the manuscript. MX conceived the hypothesis, coordinated and led the study, and participated in study design, data interpretation and in writing the manuscript.

Corresponding author

Correspondence to Maria Xilouri.

Ethics declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mavroeidi, P., Arvanitaki, F., Karakitsou, AK. et al. Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. Acta Neuropathol 138, 415–441 (2019). https://doi.org/10.1007/s00401-019-02014-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-019-02014-y

Keywords

  • Alpha-synuclein
  • Multiple system atrophy
  • Myelin
  • Oligodendrocytes
  • Seeding
  • Tubulin polymerization promoting protein