title: Sodium butyrate rescues dopaminergic cells from alpha-synuclein-induced transcriptional deregulation and DNA damage.
abstract: Alpha-synuclein (aSyn) is considered a major culprit in Parkinson's disease (PD) pathophysiology. However, the precise molecular function of the protein remains elusive. Recent evidence suggests that aSyn may play a role on transcription regulation, possibly by modulating the acetylation status of histones. Our study aimed at evaluating the impact of wild-type (WT) and mutant A30P aSyn on gene expression, in a dopaminergic neuronal cell model, and decipher potential mechanisms underlying aSyn-mediated transcriptional deregulation. We performed gene expression analysis using RNA-sequencing in Lund Human Mesencephalic (LUHMES) cells expressing endogenous (control) or increased levels of WT or A30P aSyn. Compared to control cells, cells expressing both aSyn variants exhibited robust changes in the expression of several genes, including downregulation of major genes involved in DNA repair. WT aSyn, unlike A30P aSyn, promoted DNA damage and increased levels of phosphorylated p53. In dopaminergic neuronal cells, increased aSyn expression led to reduced levels of acetylated histone 3. Importantly, treatment with sodium butyrate, a histone deacetylase inhibitor (HDACi), rescued WT aSyn-induced DNA damage, possibly via upregulation of genes involved in DNA repair. Overall, our findings provide novel and compelling insight into the mechanisms associated with aSyn neurotoxicity in dopaminergic cells, which could be ameliorated with an HDACi. Future studies will be crucial to further validate these findings and to define novel possible targets for intervention in PD.
authors.affiliation: Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Paiva
authors.affiliation: Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.|Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pinho
authors.forename: Maria Angeliki
authors.initials: MA
authors.lastname: Pavlou
authors.affiliation: Department of Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077?Göttingen, Germany.
authors.forename: Magali
authors.initials: M
authors.lastname: Hennion
authors.affiliation: Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Pauline
authors.initials: P
authors.lastname: Wales
authors.affiliation: Department of Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077?Göttingen, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Schütz
authors.affiliation: Department of Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077?Göttingen, Germany.
authors.forename: Ashish
authors.initials: A
authors.lastname: Rajput
authors.affiliation: Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Éva M
authors.initials: ÉM
authors.lastname: Szego
authors.affiliation: Department of Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), 37077?Göttingen, Germany.
authors.forename: Cemil
authors.initials: C
authors.lastname: Kerimoglu
authors.affiliation: Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: Department of Neuroscience and Disease, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Rego
authors.affiliation: Department of Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.|Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37077 Göttingen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077?Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bonn
authors.affiliation: Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.|CEDOC - Chronic Diseases Research Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.|Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D020148:Butyric Acid / Q000378:metabolism; D018929:Cell Culture Techniques; D004249:DNA Damage; D059290:Dopaminergic Neurons / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D020148:Butyric Acid