title: α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy.
abstract: Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ettle
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.|Research Center for Regenerative and Restorative Medicine, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Bilal E
authors.initials: BE
authors.lastname: Kerman
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Elvira
authors.initials: E
authors.lastname: Valera
authors.affiliation: Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Gillmann
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany.|Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Johannes C M
authors.initials: JC
authors.lastname: Schlachetzki
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Reiprich
authors.affiliation: Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Büttner
authors.affiliation: Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wegner
authors.affiliation: Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bäuerle
authors.affiliation: Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Riemenschneider
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany. juergen.winkler@uk-erlangen.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001590:Benztropine / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000187:drug effects; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; C497604:SNCA protein, human; D051844:alpha-Synuclein; D001590:Benztropine
keywords: Multiple system atrophy; Myelin; Oligodendrocyte progenitor cells; Oligodendrocytes; α-Synuclein