Acta Neuropathologica

, Volume 132, Issue 1, pp 59–75 | Cite as

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

  • Benjamin Ettle
  • Bilal E. Kerman
  • Elvira Valera
  • Clarissa Gillmann
  • Johannes C. M. Schlachetzki
  • Simone Reiprich
  • Christian Büttner
  • Arif B. Ekici
  • André Reis
  • Michael Wegner
  • Tobias Bäuerle
  • Markus J. Riemenschneider
  • Eliezer Masliah
  • Fred H. Gage
  • Jürgen Winkler
Original Paper

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.

Keywords

Multiple system atrophy Oligodendrocytes Oligodendrocyte progenitor cells Myelin α-Synuclein 

Supplementary material

401_2016_1572_MOESM1_ESM.pdf (714 kb)
Supplementary material 1 (PDF 714 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Benjamin Ettle
    • 1
  • Bilal E. Kerman
    • 2
    • 8
  • Elvira Valera
    • 3
  • Clarissa Gillmann
    • 4
  • Johannes C. M. Schlachetzki
    • 1
    • 9
  • Simone Reiprich
    • 5
  • Christian Büttner
    • 6
  • Arif B. Ekici
    • 6
  • André Reis
    • 6
  • Michael Wegner
    • 5
  • Tobias Bäuerle
    • 4
  • Markus J. Riemenschneider
    • 7
  • Eliezer Masliah
    • 3
  • Fred H. Gage
    • 2
  • Jürgen Winkler
    • 1
  1. 1.Department of Molecular NeurologyUniversity Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  2. 2.Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUSA
  3. 3.Department of NeurosciencesUniversity of California San DiegoLa JollaUSA
  4. 4.Institute of RadiologyUniversity Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  5. 5.Institute of BiochemistryFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  6. 6.Institute of Human GeneticsUniversity Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  7. 7.Department of NeuropathologyRegensburg University HospitalRegensburgGermany
  8. 8.Research Center for Regenerative and Restorative MedicineIstanbul Medipol UniversityIstanbulTurkey
  9. 9.Department of Cellular and Molecular MedicineUniversity of California San DiegoLa JollaUSA

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