p25α Relocalizes in Oligodendroglia from Myelin to Cytoplasmic Inclusions in Multiple System Atrophy

Song, Yun Ju Christine; Lundvig, Ditte M. S.; Huang, Yue; Gai, Wei; Blumbergs, Peter; Højrup, Peter; Otzen, Daniel E.; Halliday, Glenda M.; Jensen, Poul Henning

doi:10.2353/ajpath.2007.070201

Cited by 168 publications

(164 citation statements)

References 48 publications

(81 reference statements)

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“…Studies of CerS activities and other regulatory factors in sphingolipid synthesis are needed to further characterize the role of specific fatty acid chain variants in MSA and other conditions. Song and colleagues observed abnormal relocalization and breakdown of myelin-associated proteins, p25α and MBP, which appeared to precede visible GCIs formation in affected oligodendrocytes [15]. The pathogenic protein α-synuclein is a major component of GCIs in MSA oligodendrocytes and we show that its expression at the transcriptional level was upregulated selectively in the MSA-affected white matter.…”

Section: Discussionsupporting

confidence: 55%

“…Disruption of myelin structural proteins has been observed preceding visible GCIs in postmortem samples of MSA patients [15], suggesting that myelin instability may be an early event in the pathogenesis of MSA. Myelin stability in turn is dependent on the content and interassociation of its lipid constituents, particularly cholesterol and the ceramide-derived sphingolipids sphingomyelin, sulfatide and galactosylceramide [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Although lipid constitutes 78% of myelin [21] and myelin dysregulation is recognized as an important early pathological event in MSA [15], changes in lipid level/ distribution in MSA brain is unknown. In this study we assess the quantitative changes in sphingomyelin and the important structural myelin lipids sulfatide and galactosylceramide in a MSA-affected and unaffected brain region.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…GCIs contain modified AS nitrated and phosphorylated at Ser 129, which has an enhanced ability to form fibrils, while nitration may indicate a role of oxidative damage [122,521,725]. In addition to AS, GCIs and NCIs contain a large number of proteins, oligodendroglial markers, myelin basic protein (MBP), as well as p25α tubulin-polymerizationpromoting protein (TPPP) [726,727]; which promotes AS phosphorylation [728] and shows interaction with MBP (see [13,729]) (Table 3). …”

Section: Relationship Between α-Synuclein and Lewy Pathologymentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…Its activity is regulated by several post-translational modifications and its functional characteristics resemble those of microtubuleassociated proteins (MAPs) (Hlavanda et al 2007; Kleinnijenhuis et al 2008); a review on TPPP/p25 interacting partners has been given by . A connection to functions of vertebrate-specific myelin basic proteins has also been recently shown (Song et al 2007). TPPP/p25 is being intensively studied due to its role in brain function and deregulation leading to synucleinopathies, a group of neurodegenerative disorders characterized by fibrillary aggregates of α-synuclein protein in the cytoplasm of selective populations of neurons and glia (Marti et al 2003;Orosz et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Tubulin polymerization promoting protein (TPPP) ortholog from Suberites domuncula and comparative analysis of TPPP/p25 gene family

2010

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Sponges are one of the oldest metazoan phyla that are, due to their highly conservative nature, often referred to as the living fossils of multicellular animals. As such, they are a very important model for evolutionary, developmental and functional studies of Metazoa. Tubulin polymerization promoting proteins (TPPPs) are defined by the presence of p25-alpha domain (Pfam05517). Their functional characteristics resemble those of microtubule-associated proteins. Presence of TPPP homologous genes has been postulated in all eukaryotes with ciliated cells and their primary function has been proposed as some basic cilia-connected function. We present here the genomic structure and the corresponding cDNA sequence of one poriferan TPPP homolog (SdTPPP) isolated from the marine sponge Suberites domuncula; and a comparative analysis of TPPP homolog sequences and genomic structures from other Eukaryotes. Our results confirm the radiation of one TPPP homolog into three distinct genes in the Vertebrate lineage, but the origin of different sequences and their phylogenetic relationships show to be influenced by alternative protein isoforms, independent gene duplications, modularity of the p25-alpha domain and possible adaptational requirements to environmental conditions.

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p25α Relocalizes in Oligodendroglia from Myelin to Cytoplasmic Inclusions in Multiple System Atrophy

Cited by 168 publications

References 48 publications

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

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

The role of α-synuclein in neurodegeneration — An update

Tubulin polymerization promoting protein (TPPP) ortholog from Suberites domuncula and comparative analysis of TPPP/p25 gene family

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