Original article The key role of sphingosine kinases in the molecular mechanism of neuronal cell survival and death in an experimental model of Parkinson’s disease

Pyszko, Joanna; Strosznajder, Joanna B.

doi:10.5114/fn.2014.45567

Cited by 52 publications

(49 citation statements)

References 55 publications

(65 reference statements)

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“…2b,c,d). It has previously been reported that in 1-methyl-4-phenylpyridinium (MPP+) treatment of SH-SY5Y cells, an in vitro PD model, there was a significant decrease in SphK1 gene expression and that Sphk1 inhibition plays an important role in caspase-dependent apoptotic neuronal death35. However, the mRNA levels of S1P signalling molecules such as SphK1, SphK2, S1P 1 and S1P 2 receptors were unchanged under the experimental condition used in the present studies (1 μM α-Syn treatment for 18 hr) although in the proapoptotic conditions such as a higher dose (10 μM) of α-Syn or prolonged time (42 hr) treatment the mRNA level of SphK1 decreased, while that of SphK2 increased (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Extracellular α-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving β-arrestin signal intact

Zhang

Okada

Badawy

et al. 2017

Sci Rep

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The presence of α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, is the cytopathological hallmark of PD. Increasing bodies of evidence suggest that cell-to-cell transmission of α-Syn plays a role in the progression of PD. Although extracellular α-Syn is known to cause abnormal cell motility, the precise mechanism remains elusive. Here we show that impairment of platelet-derived growth factor-induced cell motility caused by extracellular α-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling. Treatment of human neuroblastoma cells with recombinant α-Syn caused S1P type 1 (S1P1) receptor-selective uncoupling from inhibitory G-protein (Gi) as determined by both functional and fluorescence resonance energy transfer (FRET)-based structural analyses. By contrast, α-Syn caused little or no effect on S1P2 receptor-mediated signalling. Both wild-type and α-Syn(A53T), a mutant found in familiar PD, caused uncoupling of S1P1 receptor, although α-Syn(A53T) showed stronger potency in uncoupling. Moreover, S1P1 receptor-mediated β-arrestin signal was unaltered by α-Syn(A53T). These results suggest that exogenous α-Syn modulates S1P1 receptor-mediated signalling from both Gi and β-arrestin signals into β-arrestin-biased signal. These findings uncovered a novel function of exogenous α-Syn in the cells.

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Section: Discussionmentioning

confidence: 99%

Extracellular α-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving β-arrestin signal intact

Zhang

Okada

Badawy

et al. 2017

Sci Rep

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“…Its pathophysiology involves, e.g., accumulation and spreading of misfolded proteins [48], neuro-inflammation including persistent microglial activity [49], neuro-inflammation including persistent microglial activity [49] and dysfunctions of mitochondrial biogenesis and quality control systems [50]. The latter processes are essentially regulated by bioactive lipids including ceramides, sphingolipids, lysophospholipids, eicosanoids, endocannabinoids, HETEs, omega-3 and omega-6 lipids and EETs [17,[51][52][53][54][55][56][57][58][59]. The relevance of subtle changes in complex regulatory circuits has been taken into account by modern omics-based analysis tools using "gene set enrichment analyses" for the detection of pattern changes [60,61].…”

Section: Discussionmentioning

confidence: 99%

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

et al. 2018

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Background: Unsupervised machine-learned analysis of cluster structures, applied using the emergent self-organizing feature maps (ESOM) combined with the unified distance matrix (U-matrix) has been shown to provide an unbiased method to identify true clusters. It outperforms classical hierarchical clustering algorithms that carry a considerable tendency to produce erroneous results. To facilitate the application of the ESOM/U-matrix method in biomedical research, we introduce the interactive R-based bioinformatics tool "Umatrix", which enables valid identification of a biologically meaningful cluster structure in the data by training a Kohonen-type self-organizing map followed by interface-guided interactive clustering on the emergent U-matrix map. Results: The ability to detect clinical relevant subgroups was applied to a data set comprising plasma concentrations of d = 25 lipid markers including endocannabinoids, lysophosphatidic acids, ceramides and sphingolipids acquired from n = 100 patients with Parkinson's disease and n = 100 controls. Following ESOM training, clear data structures in the high-dimensional data space were observed on the U-matrix, allowing separation of patients from controls almost perfectly. When the data structure was destroyed by Monte-Carlo random resampling, the U-matrix became unstructured and patients and controls were mixed. Obtained results are biologically plausible and supported by empirical evidence of a regulation of several classes of lipids in Parkinson's disease. Conclusions: Sophisticated analysis of structures in biomedical data provides a basis for the mechanistic interpretation of the observations and facilitates subsequent analyses focusing on hypothesis testing. The freely available R library "Umatrix" provides an interactive tool for broader application of unsupervised machine learning on complex biomedical data.

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“…The active principal of Nigella sativa seed thymoquinone protected dopaminergic neurons against MPP + -induced cell death in primary mesencephalic cell culture [30]. Inhibition of sphingosine kinase (Sphk1), a regulator of bioactive sphingolipid homeostasis, by SKI II protected the dopaminergic SH-SY5Y cells through an antiapoptotic pathway [29]. However, to date, there is no drug that has provided neuroprotection against dopaminergic cell loss in clinical trials [4].…”

Section: Introductionmentioning

confidence: 99%

Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture

Radad

Moldzio²,

Rausch³

2015

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Original article The key role of sphingosine kinases in the molecular mechanism of neuronal cell survival and death in an experimental model of Parkinson’s disease

Abstract: A b s t r a c t

Cited by 52 publications

References 55 publications

Extracellular α-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving β-arrestin signal intact

Extracellular α-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving β-arrestin signal intact

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture

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