A novel mouse model for investigating α-synuclein aggregates in oligodendrocytes: implications for the glial cytoplasmic inclusions in multiple system atrophy.
Animals
alpha-Synuclein
/ metabolism
Oligodendroglia
/ metabolism
Multiple System Atrophy
/ pathology
Mice, Transgenic
Inclusion Bodies
/ metabolism
Humans
Disease Models, Animal
Protein Aggregates
Green Fluorescent Proteins
/ metabolism
Cytoplasm
/ metabolism
Mice
Brain
/ pathology
Protein Aggregation, Pathological
/ metabolism
Cellular tropism
GCI
Glial cytoplasmic inclusions
MSA
Mouse model
Multiple system atrophy
Prion hypothesis
Propagation
α-synuclein
Journal
Molecular brain
ISSN: 1756-6606
Titre abrégé: Mol Brain
Pays: England
ID NLM: 101468876
Informations de publication
Date de publication:
24 May 2024
24 May 2024
Historique:
received:
18
12
2023
accepted:
20
05
2024
medline:
25
5
2024
pubmed:
25
5
2024
entrez:
24
5
2024
Statut:
epublish
Résumé
The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that αsyn accumulates not only in neurons but also in OLGs long after the administration of αsyn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial αsyn aggregates was technically difficult due to the background neuronal αsyn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of αsyn aggregates in OLGs and the comparable analysis of the cellular tropism of αsyn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human αsyn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of αsyn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial αsyn aggregates than neuronal αsyn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of αsyn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of αsyn aggregates in OLGs and could contribute to the development of therapeutics targeting αsyn aggregates in OLGs.
Identifiants
pubmed: 38790036
doi: 10.1186/s13041-024-01104-7
pii: 10.1186/s13041-024-01104-7
doi:
Substances chimiques
alpha-Synuclein
0
Protein Aggregates
0
Green Fluorescent Proteins
147336-22-9
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
28Subventions
Organisme : Moonshot Research and Development Program
ID : JPMJMS2024
Organisme : Moonshot Research and Development Program
ID : JPMJMS2024
Organisme : Japan Society for the Promotion of Science
ID : 21K20901
Organisme : Japan Society for the Promotion of Science
ID : 19K16277
Organisme : Japan Society for the Promotion of Science
ID : 20H03590
Organisme : Japan Society for the Promotion of Science
ID : 21H04816
Informations de copyright
© 2024. The Author(s).
Références
Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015;372(3):249–63.
pubmed: 25587949
doi: 10.1056/NEJMra1311488
Stefanova N, Bucke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol. 2009;8(12):1172–8.
pubmed: 19909915
doi: 10.1016/S1474-4422(09)70288-1
Jellinger KA. Neuropathology of multiple system atrophy: new thoughts about pathogenesis. Mov Disord. 2014;29(14):1720–41.
pubmed: 25297524
doi: 10.1002/mds.26052
Wenning GK, Jellinger KA. The role of alpha-synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathol. 2005;109(2):129–40.
pubmed: 15666181
doi: 10.1007/s00401-004-0935-y
Hass EW, Sorrentino ZA, Lloyd GM, McFarland NR, Prokop S, Giasson BI. Robust alpha-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy. Acta Neuropathol Commun. 2021;9(1):80.
pubmed: 33941284
pmcid: 8091528
doi: 10.1186/s40478-021-01173-y
Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–4.
pubmed: 11813001
doi: 10.1038/ncb748
Gai WP, Pountney DL, Power JH, Li QX, Culvenor JG, McLean CA, et al. alpha-Synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy. Exp Neurol. 2003;181(1):68–78.
pubmed: 12710935
doi: 10.1016/S0014-4886(03)00004-9
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–6.
pubmed: 18725592
pmcid: 2676993
doi: 10.1212/01.wnl.0000324625.00404.15
Jellinger KA. Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1. J Alzheimers Dis. 2018;62(3):1141–79.
pubmed: 28984582
pmcid: 5870010
doi: 10.3233/JAD-170397
Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci. 1989;94(1–3):79–100.
pubmed: 2559165
doi: 10.1016/0022-510X(89)90219-0
Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol. 1998;44(3):415–22.
pubmed: 9749615
doi: 10.1002/ana.410440324
Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett. 1998;249(2–3):180–2.
pubmed: 9682846
doi: 10.1016/S0304-3940(98)00407-8
Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG. Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol. 2008;64(3):239–46.
pubmed: 18825660
doi: 10.1002/ana.21465
Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T, et al. Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia. 2014;62(6):964–70.
pubmed: 24590631
pmcid: 4238782
doi: 10.1002/glia.22653
Langerveld AJ, Mihalko D, DeLong C, Walburn J, Ide CF. Gene expression changes in postmortem tissue from the rostral pons of multiple system atrophy patients. Mov Disord. 2007;22(6):766–77.
pubmed: 17290454
doi: 10.1002/mds.21259
Miller DW, Johnson JM, Solano SM, Hollingsworth ZR, Standaert DG, Young AB. Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J Neural Transm (Vienna). 2005;112(12):1613–24.
pubmed: 16284907
doi: 10.1007/s00702-005-0378-1
Ozawa T, Okuizumi K, Ikeuchi T, Wakabayashi K, Takahashi H, Tsuji S. Analysis of the expression level of alpha-synuclein mRNA using postmortem brain samples from pathologically confirmed cases of multiple system atrophy. Acta Neuropathol. 2001;102(2):188–90.
pubmed: 11563635
doi: 10.1007/s004010100367
Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338(6109):949–53.
pubmed: 23161999
pmcid: 3552321
doi: 10.1126/science.1227157
Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VM. Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med. 2012;209(5):975–86.
pubmed: 22508839
pmcid: 3348112
doi: 10.1084/jem.20112457
Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, et al. Prion-like spreading of pathological alpha-synuclein in brain. Brain. 2013;136(Pt 4):1128–38.
pubmed: 23466394
pmcid: 3613715
doi: 10.1093/brain/awt037
Paumier KL, Luk KC, Manfredsson FP, Kanaan NM, Lipton JW, Collier TJ, et al. Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers alpha-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis. 2015;82:185–99.
pubmed: 26093169
pmcid: 4640952
doi: 10.1016/j.nbd.2015.06.003
Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A, et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol. 2014;75(3):351–62.
pubmed: 24243558
doi: 10.1002/ana.24066
Shimozawa A, Ono M, Takahara D, Tarutani A, Imura S, Masuda-Suzukake M, et al. Propagation of pathological alpha-synuclein in marmoset brain. Acta Neuropathol Commun. 2017;5(1):12.
pubmed: 28148299
pmcid: 5289012
doi: 10.1186/s40478-017-0413-0
Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, et al. Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci U S A. 2015;112(38):E5308–17.
pubmed: 26324905
pmcid: 4586853
doi: 10.1073/pnas.1514475112
Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci U S A. 2013;110(48):19555–60.
pubmed: 24218576
pmcid: 3845125
doi: 10.1073/pnas.1318268110
Uemura N, Uemura MT, Lo A, Bassil F, Zhang B, Luk KC, et al. Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (alpha-Syn) Pathology in Synthetic alpha-Syn Fibril-Induced Mouse Models of Synucleinopathy. J Neuropathol Exp Neurol. 2019;78(10):877–90.
pubmed: 31504665
pmcid: 6934438
doi: 10.1093/jnen/nlz070
de Castro F, Bribián A. The molecular orchestra of the migration of oligodendrocyte precursors during development. Brain Res Brain Res Rev. 2005;49(2):227–41.
pubmed: 16111552
doi: 10.1016/j.brainresrev.2004.12.034
May VE, Ettle B, Poehler AM, Nuber S, Ubhi K, Rockenstein E, et al. alpha-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiol Aging. 2014;35(10):2357–68.
pubmed: 24698767
pmcid: 4087058
doi: 10.1016/j.neurobiolaging.2014.02.028
Kaji S, Maki T, Kinoshita H, Uemura N, Ayaki T, Kawamoto Y, et al. Pathological Endogenous alpha-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy. Stem Cell Reports. 2018;10(2):356–65.
pubmed: 29337114
pmcid: 5830961
doi: 10.1016/j.stemcr.2017.12.001
Fujishiro H, Ahn TB, Frigerio R, DelleDonne A, Josephs KA, Parisi JE, et al. Glial cytoplasmic inclusions in neurologically normal elderly: prodromal multiple system atrophy? Acta Neuropathol. 2008;116(3):269–75.
pubmed: 18553090
pmcid: 2880173
doi: 10.1007/s00401-008-0398-7
Kon T, Mori F, Tanji K, Miki Y, Wakabayashi K. An autopsy case of preclinical multiple system atrophy (MSA-C). Neuropathology. 2013;33(6):667–72.
pubmed: 23581648
doi: 10.1111/neup.12037
Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, et al. Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep. 2002;3(6):583–8.
pubmed: 12034752
pmcid: 1084143
doi: 10.1093/embo-reports/kvf109
Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, et al. Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol. 2005;166(3):869–76.
pubmed: 15743798
pmcid: 1602361
doi: 10.1016/S0002-9440(10)62307-3
Stemberger S, Poewe W, Wenning GK, Stefanova N. Targeted overexpression of human alpha-synuclein in oligodendroglia induces lesions linked to MSA-like progressive autonomic failure. Exp Neurol. 2010;224(2):459–64.
pubmed: 20493840
pmcid: 2913120
doi: 10.1016/j.expneurol.2010.05.008
Boudes M, Uvin P, Pinto S, Voets T, Fowler CJ, Wenning GK, et al. Bladder dysfunction in a transgenic mouse model of multiple system atrophy. Mov Disord. 2013;28(3):347–55.
pubmed: 23426727
pmcid: 4743066
doi: 10.1002/mds.25336
Shults CW, Rockenstein E, Crews L, Adame A, Mante M, Larrea G, et al. Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci. 2005;25(46):10689–99.
pubmed: 16291942
pmcid: 6725840
doi: 10.1523/JNEUROSCI.3527-05.2005
Hoffmann A, Ettle B, Battis K, Reiprich S, Schlachetzki JCM, Masliah E, et al. Oligodendroglial α-synucleinopathy-driven neuroinflammation in multiple system atrophy. Brain Pathol. 2019;29(3):380–96.
pubmed: 30444295
pmcid: 6850330
doi: 10.1111/bpa.12678
Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, et al. Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron. 2005;45(6):847–59.
pubmed: 15797547
doi: 10.1016/j.neuron.2005.01.032
Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A, Robinson JL, et al. Cellular milieu imparts distinct pathological alpha-synuclein strains in alpha-synucleinopathies. Nature. 2018;557(7706):558–63.
pubmed: 29743672
pmcid: 5970994
doi: 10.1038/s41586-018-0104-4
Cykowski MD, Coon EA, Powell SZ, Jenkins SM, Benarroch EE, Low PA, et al. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain. 2015;138(Pt 8):2293–309.
pubmed: 25981961
pmcid: 4840945
doi: 10.1093/brain/awv114
Nishie M, Mori F, Yoshimoto M, Takahashi H, Wakabayashi K. A quantitative investigation of neuronal cytoplasmic and intranuclear inclusions in the pontine and inferior olivary nuclei in multiple system atrophy. Neuropathol Appl Neurobiol. 2004;30(5):546–54.
pubmed: 15488031
doi: 10.1111/j.1365-2990.2004.00564.x
Sekiya H, Kowa H, Koga H, Takata M, Satake W, Futamura N, et al. Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation. Acta Neuropathol. 2019;137(3):455–66.
pubmed: 30721406
doi: 10.1007/s00401-019-01961-w
Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia. 2014;62(3):387–98.
pubmed: 24382629
doi: 10.1002/glia.22611
Caputo A, Liang Y, Raabe TD, Lo A, Horvath M, Zhang B, et al. Snca-GFP Knock-In Mice Reflect Patterns of Endogenous Expression and Pathological Seeding. eNeuro. 2020;7(4):ENEURO.0007-20.2020.
Uchihara T, Nakamura A, Mochizuki Y, Hayashi M, Orimo S, Isozaki E, et al. Silver stainings distinguish Lewy bodies and glial cytoplasmic inclusions: comparison between Gallyas-Braak and Campbell-Switzer methods. Acta Neuropathol. 2005;110(3):255–60.
pubmed: 16003542
doi: 10.1007/s00401-005-1044-2
Okuzumi A, Hatano T, Matsumoto G, Nojiri S, Ueno SI, Imamichi-Tatano Y, et al. Propagative α-synuclein seeds as serum biomarkers for synucleinopathies. Nat Med. 2023;29(6):1448–55.
pubmed: 37248302
pmcid: 10287557
doi: 10.1038/s41591-023-02358-9
Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH, Habenstein B, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575.
pubmed: 24108358
doi: 10.1038/ncomms3575
Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, et al. alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015;522(7556):340–4.
pubmed: 26061766
doi: 10.1038/nature14547
Lavenir I, Passarella D, Masuda-Suzukake M, Curry A, Holton JL, Ghetti B, et al. Silver staining (Campbell-Switzer) of neuronal alpha-synuclein assemblies induced by multiple system atrophy and Parkinson’s disease brain extracts in transgenic mice. Acta Neuropathol Commun. 2019;7(1):148.
pubmed: 31522685
pmcid: 6745790
doi: 10.1186/s40478-019-0804-5
Van der Perren A, Gelders G, Fenyi A, Bousset L, Brito F, Peelaerts W, et al. The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies. Acta Neuropathol. 2020;139(6):977–1000.
pubmed: 32356200
pmcid: 7244622
doi: 10.1007/s00401-020-02157-3
Woerman AL, Oehler A, Kazmi SA, Lee J, Halliday GM, Middleton LT, et al. Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines. Acta Neuropathol. 2019;137(3):437–54.
pubmed: 30690664
pmcid: 6454887
doi: 10.1007/s00401-019-01959-4
Yuan X, Chittajallu R, Belachew S, Anderson S, McBain CJ, Gallo V. Expression of the green fluorescent protein in the oligodendrocyte lineage: a transgenic mouse for developmental and physiological studies. J Neurosci Res. 2002;70(4):529–45.
pubmed: 12404507
doi: 10.1002/jnr.10368
Mandel RJ, Marmion DJ, Kirik D, Chu Y, Heindel C, McCown T, et al. Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates. Acta Neuropathol Commun. 2017;5(1):47.
pubmed: 28619074
pmcid: 5473003
doi: 10.1186/s40478-017-0451-7
Okuda S, Uemura N, Sawamura M, Taguchi T, Ikuno M, Uemura MT, et al. Rapid Induction of Dopaminergic Neuron Loss Accompanied by Lewy Body-Like Inclusions in A53T BAC-SNCA Transgenic Mice. Neurotherapeutics. 2022;19(1):289–304.
pubmed: 34935120
doi: 10.1007/s13311-021-01169-5
Uemura N, Yagi H, Uemura MT, Hatanaka Y, Yamakado H, Takahashi R. Inoculation of alpha-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Mol Neurodegener. 2018;13(1):21.
pubmed: 29751824
pmcid: 5948849
doi: 10.1186/s13024-018-0257-5
Ikuno M, Yamakado H, Akiyama H, Parajuli LK, Taguchi K, Hara J, et al. GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson’s disease. Hum Mol Genet. 2019;28(11):1894–904.
pubmed: 30689867
doi: 10.1093/hmg/ddz030