FTY720 (Fingolimod) reverses α-synuclein-induced downregulation of brain-derived neurotrophic factor mRNA in OLN-93 oligodendroglial cells. (1st May 2017)

• Record Type: Journal Article
• Authors: Segura-Ulate, Ismael; Yang, Barbara; Vargas-Medrano, Javier; Perez, Ruth G.
• Is Part Of: Neuropharmacology. Volume 117(2017)
• Page Start: 149
• Page End: 157
• Publication Date: 2017-05-01
• Subjects: Anti-inflammatory -- Glioprotective -- Multiple system atrophy -- Neuroprotective -- Restorative effects; AcH3 acetylated histone 3 -- aSyn α-synuclein -- BDNF brain-derived neurotrophic factor -- bp base pair -- DLB Dementia with Lewy Bodies -- FDA Food and Drug Administration -- GCI glial cytoplasmic inclusions -- HDAC histone deacetylase -- MSA Multiple System Atrophy -- PD Parkinson's disease -- rh-aSyn recombinant human wild type α-synuclein -- WT-aSyn wild type human α-synuclein -- OLG oligodendroglia -- OPC oligodendrocyte precursor cells -- RT room temperature; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.01.028
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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. Graphical abstract: Highlights: α-Synuclein (aSyn) uptake reduces BDNF mRNA levels in OLN-93 oligodendroglia cells. Wild type or A53E aSyn also reduce BDNF mRNA in OLN-93 aSyn stable cell lines. FTY720 stimulates BDNF expression in all OLN-93 aSyn stable cell lines. FTY720 acts by increasing acetylated histone 3 levels at BDNF promoter 1.