Clearance and deposition of extracellular α-synuclein aggregates in microglia

Lee, He Jin; Suk, Ji Eun; Bae, Eun Jin; Lee, Seung-Jae

doi:10.1016/j.bbrc.2008.05.045

Cited by 289 publications

(286 citation statements)

References 27 publications

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“…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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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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“…Lewy bodies and Lewy neurites, the neuropathological hallmarks of Parkinson disease and several neurological diseases, are mainly constituted by intracellular filamentous aggregates of the protein ␣-synuclein (␣-SN) 4 (1). In addition, recent studies have demonstrated the presence of misfolded or aggregated extracellular ␣-SN, suggesting that the pathogenic action of this protein might involve the transfer of ␣-SN from one cell to another through the extracellular space, with deadly consequences to the recipient cell (2)(3)(4)(5)(6). In vitro studies revealed that ␣-SN amyloid aggregation is a nucleation-dependent event that occurs in a process ranging from monomer via oligomers to fibrils (7,8).…”

mentioning

confidence: 99%

Structural Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Protofibrils Preventing α-Synuclein Oligomeric Species Toxicity

Ávila

Torres-Bugeau

Barbosa

et al. 2014

Journal of Biological Chemistry

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Background: Although glycosaminoglycan-induced GAPDH prefibrillar species accelerates ␣-synuclein aggregation, its role in toxicity remains unclear. Results: The toxic effect exerted by ␣-synuclein oligomers on cell culture was abolished by GAPDH protofibril, which was identified and structurally characterized. Conclusion: GAPDH protofibrils can efficiently sequester ␣-synuclein toxic oligomers. Significance: GAPDH protofibrils may play an important role in neuronal proteostasis and could open a novel therapeutic strategy for synucleinopathies.

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“…α-Syn is known to be taken into neurons, astrocytes and microglia and to receive clearance in these cells. 26,27) Parkin is known as the causative gene of familial PD (PARK2), and functions as a ubiquitin E3 ligase. 28) Xiong et al reported that the complex of Parkin, phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-induced putative kinase 1 (PINK1) and DJ-1 worked as a ubiquitin E3 ligase complex, and promoted proteolysis.…”

Section: Brain Damage and Potential Therapeutic Interventionsmentioning

confidence: 99%