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 54 publications

(50 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

show abstract

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 54 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

Contact Info

Product

Resources

About