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.
This study indicated that the progression level and tumor budding of ECS for cervical lymph node metastasis were useful prognostic factors in OSCC patients.
We treated a 56-year-old woman who had a right temporal lobe tumor found by chance after a traffic accident. MRI confirmed a heterogeneously enhanced tumor in the temporal lobe with large peritumoral edema extending to the superior parietal lobe. The patient underwent tumor resection. The tumor consisted largely of distinct cells with discrete borders and granular cytoplasm. In granular cells, the accumulation of PAS-positive granules was observed. Immunohistochemical analysis demonstrated positive staining for GFAP, S-100, and oligodendrocyte transcription factor 2 and negative staining for synaptophysin. CD68 was negative in granular cells, but positive in stromal cells. Ki-67 labeling index was quite low. The tumor was diagnosed as a granular cell astrocytoma (GCA). Postoperative radiotherapy combined with temozolomide was administered. One month after chemoradiotherapy, the tumor occurred in the parietal lobe, and a tumorectomy was performed. The tumor was composed of poorly differentiated astrocytic tumor cells with prominent microvascular proliferation and necrosis. A small number of granular cells were locally observed and the tumor was diagnosed as a glioblastoma. O6-methylguanine-DNA methyltransferase promoter methylation was detected in the GCA but not in the glioblastoma. Isocitrate dehydrogenase mutations were not detected in either tumor. Comparative genomic hybridization analysis demonstrated that no chromosomal abnormality was found in the GCA; however, a gain of chromosomes 7 and 19 and a loss of chromosomes 10 and 9p21 (CDKN2A) were found in the glioblastoma. p53 was strongly expressed in both the GCA and glioblastoma. The tumor progressed despite extensive chemotherapy, and the patient died 1 year after the initial treatment. Our immunohistochemical, genetic and chromosomal analyses indicate that the glioblastoma was transformed from the GCA.
Parkinson’s disease (PD) is characterized by α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies. Although it is known that extracellular α-Syn is detected in the plasma and cerebrospinal fluid, its physiological significance remains unclear. Here, we show that extracellular α-Syn suppresses platelet-derived growth factor (PDGF)-induced chemotaxis in human neuroblastoma SH-SY5Y cells. The inhibitory effect was stronger in the mutant α-Syn(A53T), found in hereditary PD, and the degree of inhibition was time-dependent, presumably because of the oligomerization of α-Syn. PDGF-induced activation of Akt or Erk was not influenced by α-Syn(A53T). Further studies revealed that α-Syn(A53T) inhibited PDGF-induced Rac1 activation, whereas Cdc42 activation remained unaffected, resulting in unbalanced actin filament remodeling. These results shed light on the understanding of pathological as well as physiological functions of extracellular α-Syn in neuronal cells.
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