FTY720 (Fingolimod) reverses α-synuclein-induced downregulation of brain-derived neurotrophic factor mRNA in OLN-93 oligodendroglial cells.
FTY720 (Fingolimod) reverses α-synuclein-induced downregulation of brain-derived neurotrophic factor mRNA in OLN-93 oligodendroglial cells.
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DOI：
10.1016/j.neuropharm.2017.01.028
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发表时间：
2017-05-01
影响因子：
4.7
通讯作者：
Perez RG
中科院分区：
文献类型：
--
作者：
Segura-Ulate I;Yang B;Vargas-Medrano J;Perez RG
多系统萎缩（MSA）是一种脱髓鞘性神经退行性疾病，其特征是α-突触核蛋白（aSyn）聚集在少突胶质细胞前体、成熟少突胶质细胞和神经元内。MSA功能障碍与胶质细胞和神经元细胞营养因子生成的丧失有关。在这里，我们报告了重组野生型人少突胶质细胞OLN-93摄取aSyn，降低了脑源性神经营养因子（BDNF）的表达。此外，OLN-93细胞稳定转染了人类野生型或msa相关突变体aSyn， A53E，产生神经元和胶质包涵体，将BDNF mRNA降低到几乎不可测量的qPCR水平。奇怪的是，另一种与msa相关的aSyn突变体G51D也产生神经元和胶质包涵体，在转染的OLN-93细胞中只引起BDNF mRNA减少的趋势。这表明少突胶质细胞相关的BDNF损失发生在特定的aSyn类型的反应中。160 nM FTY720 （Fingolimod, Gilenya®）是美国食品和药物管理局（FDA）批准的多发性硬化症治疗药物，用于治疗OLN-93细胞，抵消了所有aSyn OLN-93细胞中的BDNF下调。通过琼脂糖凝胶的qPCR或半定量检测，FTY720也能恢复重组aSyn处理的OLN-93细胞中的BDNF mRNA。免疫印迹证实FTY720增加了OLN-93中组蛋白3的乙酰化，染色质免疫沉淀试验显示FTY720后BDNF启动子1中组蛋白3的乙酰化增加。此外，用丙戊酸（一种经典的组蛋白去乙酰化酶抑制剂）处理的OLN-93细胞证实，乙酰化组蛋白3水平的增加会增加BDNF的表达。总的来说，数据表明FTY720相关的组蛋白去乙酰化酶抑制刺激少突胶质细胞中BDNF的表达，这提高了MSA患者也可能从FTY720治疗中获益的可能性。
Multiple system atrophy (MSA) is a demyelinating neurodegenerative disorder characterized by accumulation of aggregated α-synuclein (aSyn) inside oligodendrocyte precursors, mature oligodendroglia, and neurons. MSA dysfunction is associated with loss of trophic factor production by glial and neuronal cells. Here, we report that recombinant wild type human aSyn uptake by OLN-93, an oligodendroglia cell-line, reduced brain-derived neurotrophic factor (BDNF) expression. Furthermore, OLN-93 cells stably transfected with human wild type or an MSA-associated mutant aSyn, A53E that produces neuronal and glial inclusions, reduced BDNF mRNA to nearly unmeasurable qPCR levels. Curiously, another MSA-associated aSyn mutant, G51D that also produces neuronal and glial inclusions, caused only a trend toward BDNF mRNA reduction in transfected OLN-93 cells. This suggests that oligodendrocyte-associated BDNF loss occurs in response to specific aSyn types. Treating OLN-93 cells with 160 nM FTY720 (Fingolimod, Gilenya®), a Food and Drug Administration (FDA) approved therapeutic for multiple sclerosis, counteracted BDNF downregulation in all aSyn OLN-93 cells. FTY720 also restored BDNF mRNA in OLN-93 cells treated with recombinant aSyn, as measured by qPCR or semiquantitatively on agarose gels. Immunoblots confirmed that FTY720 increased histone 3 acetylation in OLN-93, and chromatin immunoprecipitation assays showed increased acetylated histone 3 at BDNF promoter 1 after FTY720. Moreover, OLN-93 cells treated with valproic acid, a classic histone deacetylase inhibitor, confirmed that increasing acetylated histone 3 levels increases BDNF expression. Cumulatively, the data suggest that FTY720-associated histone deacetylase inhibition stimulates BDNF expression in oligodendroglial cells, raising the possibility that MSA patients may also benefit by treatment with FTY720.
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影响因子：
5.9
作者：
Djelloul M;Holmqvist S;Boza-Serrano A;Azevedo C;Yeung MS;Goldwurm S;Frisén J;Deierborg T;Roybon L
通讯作者：
Roybon L
影响因子：
6.8
作者：
Efstathopoulos P;Kourgiantaki A;Karali K;Sidiropoulou K;Margioris AN;Gravanis A;Charalampopoulos I
通讯作者：
Charalampopoulos I
影响因子：
6.2
作者：
Hait NC;Avni D;Yamada A;Nagahashi M;Aoyagi T;Aoki H;Dumur CI;Zelenko Z;Gallagher EJ;Leroith D;Milstien S;Takabe K;Spiegel S
通讯作者：
Spiegel S
影响因子：
3.5
作者：
Di Pardo, Alba;Amico, Enrico;Maglione, Vittorio
通讯作者：
Maglione, Vittorio
影响因子：
6.2
作者：
Jung, C. G.;Kim, H. J.;Soliven, B.
通讯作者：
Soliven, B.