Absence of α-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia

Miller, David W.; Johnson, Jennifer M.; Solano, Steven M.; Hollingsworth, Zane R.; Standaert, David G.; Young, Anne B.

doi:10.1007/s00702-005-0378-1

Cited by 166 publications

(129 citation statements)

References 32 publications

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“…In multiple system atrophy, another synucleinopathy, ␣-synuclein-positive inclusions, called glial cytoplasmic inclusions, are generated in oligodendrocytes (44). Astrocytes and oligodendrocytes appear to express ␣-synuclein protein, but the level of expression is much lower than in neurons (9,10). The low level endogenous ␣-synuclein expression in glial cells has prompted a debate as to the origin of the glial ␣-synuclein deposition.…”

Section: Discussionmentioning

confidence: 99%

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Lee

Suk²,

Patrick

et al. 2010

Journal of Biological Chemistry

717

726

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Abnormal neuronal aggregation of ␣-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive ␣-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial ␣-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that ␣-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of ␣-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human ␣-synuclein. Furthermore, astrocytes that were exposed to neuronal ␣-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of ␣-synuclein. Together, these results suggest that astroglial ␣-synuclein pathology is produced by direct transmission of neuronal ␣-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Lee

Suk²,

Patrick

et al. 2010

Journal of Biological Chemistry

717

726

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“…However, a more simple explanation is that the heterologous Prnp promoter that drives mutant α-synuclein expression in TgM83 mice does not engender a native spatial pattern of α-synuclein expression. This difference may preclude deposition in mature oligodendrocytes, which do not express α-synuclein mRNA (31). Inoculation of Tg mice expressing A53T mutant human α-synuclein under the control of the SNCA promoter or even non-Tg mice with MSA brain homogenate may help to resolve this issue.…”

Section: Discussionmentioning

confidence: 99%

Transmission of multiple system atrophy prions to transgenic mice

Watts

Giles

Oehler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

373

397

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Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson's disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83 +/+ mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83 +/− mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83 +/− mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83 +/− mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83 +/+ mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.neurodegeneration | bioluminescence imaging | seeding | proteinopathies

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“…Although the evidence of significant physiological expression of α-synuclein in mature oligodendrocytes is conflicting [45][46][47], it has been proposed that upregulation of the SNCA gene in these cells could be the cause of GCI formation. However, there appears to be no dysregulation of α-synuclein expression in the MSA disease state.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, successful animal models of MSA, which recapitulate neuropathological features, have been generated by α-synuclein overexpression in the oligodendrocytes of mouse brains [48][49][50]. Alternatively, aberrant uptake of α-synuclein protein from the extracellular environment has also been proposed as a possible mechanism of GCI formation [45,51,52]. Separate lines of evidence from transgenic mouse models support the specific functional importance of myelin sulfatide content in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

Don

Hsiao

Bleasel

et al. 2014

Acta Neuropathologica Communications

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Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of α-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40-69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased α-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.

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Absence of α-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia

Cited by 166 publications

References 32 publications

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Transmission of multiple system atrophy prions to transgenic mice

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

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