title: Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells.
abstract: Myelin loss is a widespread neuropathological hallmark of the atypical parkinsonian disorder multiple system atrophy (MSA). On a cellular level, MSA is characterized by alpha-synuclein (aSyn)-positive glial cytoplasmic inclusions (GCIs) within mature oligodendrocytes leading to demyelination as well as axonal and neuronal loss. Oligodendrocyte progenitor cells (OPCs) represent a proliferative cell population distributed throughout the adult mammalian central nervous system. During remyelination, OPCs are recruited to sites of demyelination, differentiate, and finally replace dysfunctional mature oligodendrocytes. However, comprehensive studies investigating OPCs and remyelination processes in MSA are lacking. In the present study, we therefore investigate the effect of human aSyn (h-aSyn) on early primary rat OPC maturation. Upon lentiviral transduction, h-aSyn expressing OPCs exhibit fewer and shorter primary processes at the initiation of differentiation. Until day 4 of a 6day differentiation paradigm, h-aSyn expressing OPCs further show a severely delayed maturation evidenced by reduced myelin gene expression and increased levels of the progenitor marker platelet derived growth factor receptor-alpha (PDGFRα). Matching these results, OPCs that take up extracellular recombinant h-aSyn exhibit a similar delayed differentiation. In both experimental setups however, myelin gene expression is restored at day 6 of differentiation paralleled by decreased intracellular h-aSyn levels indicating a reverse correlation of h-aSyn and the differentiation potential of OPCs. Taken together, these findings suggest a tight link between the intracellular level of h-aSyn and maturation capacity of primary OPCs.
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ettle
authors.affiliation: Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Reiprich
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Deusser
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Johannes C M
authors.initials: JC
authors.lastname: Schlachetzki
authors.affiliation: Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: IZKF Junior Group III and BMBF Research Group Neurosciences, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Prots
authors.affiliation: Department of Neurosciences and Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: IZKF Junior Group III and BMBF Research Group Neurosciences, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.affiliation: Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wegner
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: juergen.winkler@uk-erlangen.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism*; D017208:Rats, Wistar; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D004676:Myelin Basic Protein; C497606:Snca protein, rat; D051844:alpha-Synuclein
keywords: Alpha-synuclein; Maturation; Multiple system atrophy; Myelin basic protein; Oligodendrocyte progenitor cells