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.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Mavroeidi P,Arvanitaki F,Karakitsou AK,Vetsi M,Kloukina I,Zweckstetter M,Giller K,Becker S,Sorrentino ZA,Giasson BI,Jensen PH,Stefanis L,Xilouri Mdoi
10.1007/s00401-019-02014-ysubject
Has Abstractpub_date
2019-09-01 00:00:00pages
415-441issue
3eissn
0001-6322issn
1432-0533pii
10.1007/s00401-019-02014-yjournal_volume
138pub_type
杂志文章abstract::Transient forebrain ischemia produces a spatially and temporally selective pattern of neuronal degeneration in the hippocampal formation of the Mongolian gerbil. Ischemic neuronal death has been suggested to depend on the activation of excitatory hippocampal pathways that project to the vulnerable neurons. This idea w...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687758
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abstract::Two distinct species of amyloid beta protein (A beta) with different carboxyl termini, A beta 40 and A beta 42(43), are deposited in plaques in the brains of patients with Alzheimer's disease and Down's syndrome. The relationship between these two forms of A beta and microglial cells was investigated in 16 subjects wi...
journal_title:Acta neuropathologica
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abstract::With an incidence of approximately 350 in 100,000, stroke is the third leading cause of death and a major cause of disability in industrialized countries. At present, although progress has been made in understanding the molecular pathways that lead to ischemic cell death, the current clinical treatments remain poorly ...
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abstract::It is conventionally accepted that during the early stages of Wallerian degeneration of myelinated peripheral nerve fibres Schmidt-Lanterman incisures represent the sites at which the myelin sheath, together with enclosed axoplasm, is segmented into myelin ovoids. This mechanism is considered by some authors to be fac...
journal_title:Acta neuropathologica
pub_type: 杂志文章
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abstract::Emerging evidence has demonstrated the neuroprotection of estrogen in Alzheimer's disease (AD). The hippocampus, an important target of estrogen action, is severely affected in the Alzheimer process. The aim of present study was to detect the distribution of estrogen receptor-alpha (ER-alpha) and the relationship betw...
journal_title:Acta neuropathologica
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doi:10.1007/s00401-003-0720-3
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abstract::We describe three cases of early- (cases 1-3, 28-39 years) and one of late-onset (case 4, 76 years) Alzheimer's disease (AD) with 'cotton wool' plaques (CWPs) but without a family history indicating autosomal dominant inheritance. The early-onset cases, but not the late-onset case, showed remarkable aggression, disinh...
journal_title:Acta neuropathologica
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doi:10.1007/s00401-003-0737-7
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abstract::In almost all of the earlier reported cases of Kufs' disease, the adult form of ceroid lipofuscinosis, the diagnosis was ascertained by cerebral tissue examination, while peripheral biopsy examination revealed an apparent poor diffusion of specific lipofuscinic deposits, the finger print profiles (FPs). We report the ...
journal_title:Acta neuropathologica
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doi:10.1007/s004010050866
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abstract::Gliomas induced in the rat by transplacental administration of ethylnitrosourea (ENU) are intensely immunoreactive for vimentin and scarcely for glial fibrillary acidic protein (GFAP). Since tumoral transformation takes place during the late fetal and early postnatal period, the sequential expression of the two glial ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00227665
更新日期:1992-01-01 00:00:00
abstract::The expression of glial fibrillary acidic protein (GFAP) in continuous glioma and non-glioma cell lines was evaluated by molecular hybridization and immunocytochemistry. RNA transcripts from the GFAP gene were detected in two of six cell lines by Northern blot analysis of cellular RNAs using a cloned mouse GFAP cDNA p...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688264
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journal_title:Acta neuropathologica
pub_type: 杂志文章
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686387
更新日期:1988-01-01 00:00:00
abstract::A human glioma cell line, SA146, was initiated on precoated extracellular matrix from a stereotactic biopsy of a glioblastoma. We report modulation in the expression of glial fibrillary acidic protein (GFAP) by SA146 passed in vitro before or after xenogenic transplantation into nude mice. Immunofluorescence data show...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050722
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abstract::Primary extradural ependymomas are rare neoplasms usually of the myxopapillary type. Reports on malignant primary extradural ependymal tumors are exceptionally rare. We here report on a 3-year-old boy with Schinzel-Giedion syndrome (SGS), who presented with lumbar spina bifida occulta and a progressive extraspinal les...
journal_title:Acta neuropathologica
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abstract::An extensive laminar spongiosis was found in the outer part of the dentate gyrus in an 84-year-old patient. An old cavitary infarct in the parahippocampal gyrus disconnected the dentate gyrus from the entorhinal area. This finding prompted us to seek laminar spongiosis in Alzheimer's disease, where the neuronal loss i...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050818
更新日期:1998-04-01 00:00:00
abstract::Experimental allergic neuritis (EAN) was induced in normal and irradiated Lewis rats by passively transferring T cells sensitized to SP-26, a peptide fragment of P2 myelin protein. The recipients became sick 4-8 days post transfer and the degree of disability correlated directly with the dose of T cells. Smaller doses...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294298
更新日期:1993-01-01 00:00:00
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journal_title:Acta neuropathologica
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doi:10.1007/s00401-004-0900-9
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-017-1737-3
更新日期:2017-11-01 00:00:00
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00692214
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journal_title:Acta neuropathologica
pub_type: 杂志文章
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687575
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00307635
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00689508
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294437
更新日期:1991-01-01 00:00:00
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journal_title:Acta neuropathologica
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doi:10.1007/s00401-016-1550-4
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journal_title:Acta neuropathologica
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doi:10.1007/s00401-006-0056-x
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294647
更新日期:1990-01-01 00:00:00
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010051104
更新日期:1999-10-01 00:00:00
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journal_title:Acta neuropathologica
pub_type: 杂志文章
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