The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle

Ma, Kaili; Song, Lian-Kun; Yuan, Yu‐He; Zhang, Ying; Han, Ning; Gao, Kai; Chen, Nai‐Hong

doi:10.1016/j.neuropharm.2013.07.035

Cited by 50 publications

(56 citation statements)

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“…However, the functional or pathological implications of nuclear α-Syn are unclear. Ma et al suggest that residues (103–140) located at the C-terminus of α-Syn are critical for its nuclear localization [22]. They have also proposed involvement of importin α, a nuclear-transport receptor protein, in the translocation of α-Syn into the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…α-Syn is localized predominantly in the neuronal cytosol and is membrane-bound in presynaptic nerve terminals, although several studies identified a small fraction of the protein in other cellular compartments, including the mitochondria and the nucleus [16–22]. Although there are discrepancies in the literature about the presence of α-Syn in the nuclei of healthy neurons, presumably due to varying sensitivity of the detection methods employed, there is more consistent evidence supporting its nuclear localization in PD-affected neurons [23–25].…”

Section: Introductionmentioning

confidence: 99%

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Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Vasquez

Mitra

Hegde

et al. 2017

JAD

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Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson’s disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (~2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Vasquez

Mitra

Hegde

et al. 2017

JAD

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“…Total proteins were extracted as previously described [17] . PC12 cells were lysed in NP-40 lysis buffer (150 mmol/L NaCl, 1% Nonidet P-40, 50 mmol/L Tris, pH 7.4, and 1 mmol/L ethylenediamine tetraacetic acid) with a proteinase inhibitor cocktail (SigmaAldrich, St Louis, MO, USA).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…After washing the cells with PBS three times, the cells were incubated with an Alexa Fluor 488-conjugated secondary antibody, an Alexa Fluor 546-conjugated secondary antibody (1:500, Invitrogen, New York, USA) and Hoechst 33342 (1:1000, Life Technologies, NY, USA) for 1 h at room temperature. Images were obtained using a Leica inverted microscope equipped for fluorescence analysis (Leica Microsystems, Germany) [17] . …”

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Bibenzyl compound 20c protects against endoplasmic reticulum stress in tunicamycin-treated PC12 cells in vitro

et al. 2016

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Aim: Accumulation of α-synuclein (α-syn) in the brain is a characteristic of Parkinson's disease (PD). In this study, we investigated whether treatment with tunicamycin, an endoplasmic reticulum (ER) stress inducer, led to the accumulation of α-syn in PC12 cells, and where α-syn protein was accumulated, and finally, whether bibenzyl compound 20c, a novel compound isolated from Gastrodia elata (Tian ma), could alleviate the accumulation of α-syn and ER stress activation in tunicamycin-treated PC12 cells. Methods: PC12 cells were treated with tunicamycin for different time (6 h, 12 h, 24 h, 48 h). Cell viability was determined by a MTT assay. Subcellular fractions of ER and mitochondria were extracted with the Tissue Endoplasmic reticulum Isolation Kit. The levels of α-syn protein and ER-stress-associated downstream chaperones were detected using Western blots and immunofluorescence. Results: Treatment of PC12 cells with tunicamycin (0.5-10 μg/mL) dose-dependently increased the accumulation of α-syn monomer (19 kDa) and oligomer (55 kDa), and decreased the cell viability. Accumulation of the two forms of α-syn was observed in both the ER and mitochondria with increasing treatment time. Co-treatment with 20c (10 -5 mol/L) significantly increased the viability of tunicamycintreated cells, reduced the level of α-syn protein and suppressed ER stress activation in the cells, evidenced by the reductions in phosphorylation of eIF2α and expression of spliced ATF6 and XBP1. Conclusion: Tunicamycin treatment caused accumulation of α-syn monomer and oligomer in PC12 cells. Bibenzyl compound 20c reduces the accumulation of α-syn and inhibits the activation of ER stress, which protected PC12 cells against the toxicity induced by tunicamycin.Keywords: Gastrodia elata; bibenzyl compound 20c; PC12 cells; tunicamycin; α-synuclein; ER stress; Parkinson's disease; neuroprotection Acta Pharmacologica Sinica (2016Sinica ( ) 37: 1525Sinica ( -1533 doi: 10.1038/aps.2016 proteins in the ER [6,7] . The activation of the PERK pathway promotes the phosphorylation of eIF2α and the expression of transcription factor ATF4, which increases the expression of ER chaperones to reduce protein entry into the ER. During ER stress, ATF6 translocates to the Golgi and releases transcription factors to migrate into the nucleus and regulate gene expression. When IRE1 is activated, it catalyzes the splicing of the mRNA encoding the X-box-binding protein 1 (XBP1) to produce XBP1 and regulate target genes [8] . Although the mechanisms of PD pathogenesis remain unclear, many studies have indicated that the accumulation of α-syn may be a neurotoxic factor [9,10] . However, the mechanisms underlying α-syn accumulation and how α-syn accumulation contributes to neurodegeneration remain poorly understood. Studies have indicated that sodium butyrate, which is an ER stress inducer, can induce an increase in the oligomeric forms of α-syn in 3D5 cells, and this effect was blocked by cotreatment with the ER stress inhibitor salubrinal, which suggested that ER stress co...

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DNA damage and repair in Parkinson's disease: Recent advances and new opportunities

Gonzalez‐Hunt

Sanders

2020

J of Neuroscience Research

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Parkinson's disease (PD) is the most common movement neurodegenerative disorder. Although our understanding of the underlying mechanisms of pathogenesis in PD has greatly expanded, this knowledge thus far has failed to translate into disease‐modifying therapies. Therefore, it is of the utmost urgency to interrogate further the multifactorial etiology of PD. DNA repair defects cause many neurodegenerative diseases. An exciting new PD research avenue is the role that DNA damage and repair may play in neuronal death. The goal of this mini‐review was to discuss the evidence for the types of DNA damage that accumulates in PD, which has provided clues for which DNA repair pathways, such as DNA double‐strand break repair, are dysfunctional. We further highlight compelling data for activation of the DNA damage response in familial and idiopathic PD. The significance of DNA damage and repair is emerging in the PD field and linking these insights to PD pathogenesis may provide new insights into PD pathophysiology and consequently lead to new therapies.

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The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle

Cited by 50 publications

References 53 publications

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Bibenzyl compound 20c protects against endoplasmic reticulum stress in tunicamycin-treated PC12 cells in vitro

DNA damage and repair in Parkinson's disease: Recent advances and new opportunities

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