Nuclear Localization of α-Synuclein and Its Interaction with Histones

Goers, John; Manning-Bog, Amy; McCormack, Alison L.; Millett, Ian S.; Doniach, Sebastian; Monte, Donato A. Di; Uversky, Vladimir N.; Fink, Anthony L.

doi:10.1021/bi0341152

Cited by 313 publications

(306 citation statements)

References 31 publications

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“…One possibility might be interference with transcriptional machinery. In support of this, ␣-syn has been found to be associated with histone proteins (Goers et al, 2003) and affects both their acetylation and expression levels (Goers et al, 2003;Duce et al, 2006;Kontopoulos et al, 2006;Vartiainen et al, 2006). Although ␣-syn is almost exclusively present in nerve terminals during adulthood (Iwai et al, 1994), it has been found in the perikarya during development (Hsu et al, 1998;Galvin et al, 2001;Raghavan et al, 2004).…”

Section: Discussionmentioning

confidence: 80%

α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

Crews¹,

Mizuno²,

Desplats³

et al. 2008

J. Neurosci.

126

109

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Section: Discussionmentioning

confidence: 80%

α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

Crews¹,

Mizuno²,

Desplats³

et al. 2008

J. Neurosci.

126

109

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“…These data support the view that transcriptional dysregulation is an important consequence of α-syn overexpression and, therefore, may be critical to the pathogenesis of synucleinopathies. Alphasyn has been identified within cell nuclei and has been shown to associate with histones in vitro (Goers et al, 2003;Maroteaux et al, 1988). Studies by Kontopoulos et al (2006) have provided direct evidence that α-syn can inhibit histone acetylation in both mammalian cell culture models and transgenic Drosophila.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional dysregulation in a transgenic model of Parkinson disease

Yacoubian

Cantuti-Castelvetri

Bouzou

et al. 2008

Neurobiology of Disease

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Alpha-synuclein has been implicated in Parkinson's disease, yet the mechanism by which alphasynuclein causes cell injury is not understood. Using a transgenic mouse model, we evaluated the effect of alpha-synuclein overexpression on gene expression in the substantia nigra. Nigral mRNA from wildtype and alpha-synuclein transgenic mice was analyzed using Affymetrix gene arrays. At three months, before pathological changes are apparent, we observed modest alterations in gene expression. However, nearly 200 genes were altered in expression at nine months, when degenerative changes are more apparent. Functional genomic analysis revealed that the genes altered at nine months were predominantly involved in gene transcription. As in human Parkinson's disease, gene expression changes in the transgenic model were also modulated by gender. These data demonstrate that alterations of gene expression are widespread in this animal model, and suggest that transcriptional dysregulation may be a disease mechanism that can be targeted therapeutically.

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“…In particular, nuclear localization of α-Syn increases under oxidative stress conditions [112,114,115]. Nuclear α-Syn interacts with histones, inhibits acetylation, and promotes neurotoxicity [116,117]. Furthermore, α-Syn may act as a transcriptional regulator, binding promoters such as PGC1-α, a master regulator of mitochondrial gene expression [106].…”

Section: Phosphorylation At Serine129 Modulates α-Synuclein Protein-pmentioning

confidence: 99%

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

Ganapathy¹

2017

Protein Phosphorylation

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Post-translational protein modifications play an important role in generating the large diversity of the proteome in comparison to the relatively small number of genes; phosphorylation being the most widespread. Phosphorylation of proteins regulates important molecularswitches for several cellular events and abnormal phosphorylation events are associated in many neurodegenerative diseases. In Parkinson's disease (PD) the main hallmark is the accumulation of cytoplasmic inclusions, Lewy bodies (LBs), consisting of α-synuclein (α-Syn) and ubiquitin. There's another key observation which is increasingly gaining prominence is a modified-form of α-Syn; the phospho α-Syn serine129 (pSyn). The significance of pSyn has gained importance in PD because its accumulation is distinctly enhanced in the diseased condition. The revelation of the involvement of pSyn on α-Syn aggregation, LB formation and neurotoxicity is crucial to understanding the pathogenesis and progression of PD. Since some in vitro and in vivo studies have indicated that pSyn is an early event preceding apoptosis, some important questions now needs to be explored in reference to the physiological functions regulated by phosphorylation, such as dopamine synthesis, vesicle mobilization, regulation of synaptic proteins, and synaptic plasticity. An investigation of the role of enzymes on the phosphorylation and clearance of α-Syn and region-specific susceptibility is required to be determined; to identify viable targets for new therapeutics.

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Nuclear Localization of α-Synuclein and Its Interaction with Histones

Cited by 313 publications

References 31 publications

α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

α-Synuclein Alters Notch-1 Expression and Neurogenesis in Mouse Embryonic Stem Cells and in the Hippocampus of Transgenic Mice

Transcriptional dysregulation in a transgenic model of Parkinson disease

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

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