Translocation of Distinct Alpha Synuclein Species from the Nucleus to Neuronal Processes during Neuronal Differentiation

Pieger, Katharina; Schmitt, Verena; Gauer, Carina; Gießl, Nadja; Prots, Iryna; Winner, Beate; Winkler, Jürgen; Brandstätter, Johann Helmut; Xiang, Wei

doi:10.3390/biom12081108

Cited by 4 publications

(5 citation statements)

References 58 publications

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“…In contrast, in this study, we revealed that the accumulation of αSyn in the cytosol and nucleus could result in distinct cytotoxicities in MEF. Several studies have reported that the presence of αSyn in the nucleus of cells may underlie αSyn-derived neurodegeneration [6][7][8][9]. We demonstrated that the nucleus-localized αSyn promoted similar cytotoxicity as described in previous studies [7][8][9], and was related to the abnormal rRNA processing and elevated ribosomal protein in this study (Figure 8).…”

Section: Discussionsupporting

confidence: 88%

“…Several studies have reported that the presence of αSyn in the nucleus of cells may underlie αSyn-derived neurodegeneration [6][7][8][9]. We demonstrated that the nucleus-localized αSyn promoted similar cytotoxicity as described in previous studies [7][8][9], and was related to the abnormal rRNA processing and elevated ribosomal protein in this study (Figure 8). Thus, the neurotoxicity of nuclear αSyn might be mediated via ribosomal biogenesis, and the accumulated cytosolic αSyn would propagate the spread of alpha-synucleinopathy and neuroinflammation by the disruption of autophagy-lysosomal degradation pathway.…”

Section: Discussionsupporting

confidence: 88%

“…αSyn is a major component of Lewy bodies (LB) and Lewy neurites (LN). Most αSyn aggregating in vitro in LB and LN was found in the cytoplasm; however, some αSyn was localized in the nucleus [6][7][8][9]. In previous studies, nuclear αSyn manifested toxic effects on cells [7].…”

Section: Introductionmentioning

confidence: 89%

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Nuclear α-Synuclein-Derived Cytotoxic Effect via Altered Ribosomal RNA Processing in Primary Mouse Embryonic Fibroblasts

Kim

Nam

et al. 2023

IJMS

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α-Synuclein (αSyn) is an important player in Parkinson’s disease (PD) pathogenesis. The aggregation of αSyn is mainly formed in the cytoplasm, whereas some αSyn accumulation has also been found in the nuclei of neurons. To assess the effect of nuclear αSyn, we generated αSyn conjugated with a nuclear export signal (NES) or a nuclear localization signal (NLS), and compared them with wild-type αSyn in primary mouse embryonic fibroblasts (MEF) using DNA transfection. Overexpression of NLS-αSyn increased cytotoxicity. The levels of apoptotic markers were increased by NLS-αSyn in MEF. Interestingly, an increase in the levels of 40S ribosomal protein 15 was observed in MEF expressing NLS-αSyn. These MEF also showed a higher 28S/18S rRNA ratio. Intriguingly, the expression of NLS-αSyn in MEF enhanced segmentation of nucleolin (NCL)-positive nucleolar structures. We also observed that the downregulation of NCL, using shRNA, promoted a relatively higher 28S/18S rRNA ratio. The reduction in NCL expression accelerated the accumulation of αSyn, and NCL transfection enhanced the degradation of αSyn. These results suggest that nuclear αSyn contributes to the alteration in ribosomal RNA processing via NCL malfunction-mediated nucleolar segmentation, and that NCL is a key factor for the degradation of αSyn.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

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Nuclear α-Synuclein-Derived Cytotoxic Effect via Altered Ribosomal RNA Processing in Primary Mouse Embryonic Fibroblasts

Kim

Nam

et al. 2023

IJMS

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“…In the case of RNAi-knockdown, floating cells were transfected with Lipofectamine ™ RNAiMAX (Thermofisher Scientific, Grand Island, New York, NK, USA) and medium was changed the next day. To separate nuclear and cytosolic proteins, cells were homogenized and fractionated as previously described [48].…”

Section: Nuclear and Cytoplasmic Separation Of Proteinmentioning

confidence: 99%

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Devitt,

Westphal,

Pieger

et al. 2024

Cell Commun Signal

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Background Melanoma is a highly heterogeneous cancer, in which frequent changes in activation of signaling pathways lead to a high adaptability to ever changing tumor microenvironments. The elucidation of cancer specific signaling pathways is of great importance, as demonstrated by the inhibitor of the common BrafV600E mutation PLX4032 in melanoma treatment. We therefore investigated signaling pathways that were influenced by neurotrophin NRN1, which has been shown to be upregulated in melanoma. Methods Using a cell culture model system with an NRN1 overexpression, we investigated the influence of NRN1 on melanoma cells’ functionality and signaling. We employed real time cell analysis and spheroid formation assays, while for investigation of molecular mechanisms we used a kinase phosphorylation kit as well as promotor activity analysis followed by mRNA and protein analysis. Results We revealed that NRN1 interacts directly with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing a potential retention of NICD in the cytoplasm and thereby reducing the expression of its direct downstream target Hes1. This leads to decreased sequestration of JAK and STAT3 in a Hes1-driven phosphorylation complex. Consequently, our data shows less phosphorylation of STAT3 while presenting an accumulation of total protein levels of STAT3 in association with NRN1 overexpression. The potential of the STAT3 signaling pathway to act in both a tumor suppressive and oncogenic manner led us to investigate specific downstream targets – namely Vegf A, Mdr1, cMet - which were found to be upregulated under oncogenic levels of NRN1. Conclusions In summary, we were able to show that NRN1 links oncogenic signaling events between Notch and STAT3 in melanoma. We also suggest that in future research more attention should be payed to cellular regulation of signaling molecules outside of the classically known phosphorylation events. Graphical Abstract

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“…Besides phosphorylation, SUMOylation, which is generated by mature small ubiquitin-related modifiers (SUMO), may occur during the nuclear translocation of αS [ 58 ]. Interestingly, distinct αS species translocate from the nucleus to neuronal processes during neuronal differentiation, which suggests that the maturation process of the nervous system may affect subcellular localization [ 59 ]. With respect to protein conformational change and aggregation, exposure to human fibrotic αS seed facilitates the formation of intranuclear inclusions in mouse primary cortical neurons [ 60 ].…”

Section: Interaction Between αS and Epigenetic Factorsmentioning

confidence: 99%

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

Sugeno

Hasegawa

2023

IJMS

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Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson’s disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.

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Translocation of Distinct Alpha Synuclein Species from the Nucleus to Neuronal Processes during Neuronal Differentiation

Cited by 4 publications

References 58 publications

Nuclear α-Synuclein-Derived Cytotoxic Effect via Altered Ribosomal RNA Processing in Primary Mouse Embryonic Fibroblasts

Nuclear α-Synuclein-Derived Cytotoxic Effect via Altered Ribosomal RNA Processing in Primary Mouse Embryonic Fibroblasts

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

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