α-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy.
Multiple system atrophy (MSA), an atypical parkinsonian disorder, is characterized by α-synuclein (α-syn(+)) cytoplasmatic inclusions in mature oligodendrocytes. Oligodendrocyte progenitor cells (OPCs) represent a distinct cell population with the potential to replace dysfunctional oligodendrocytes. However, the role of OPCs in MSA and their potential to replace mature oligodendrocytes is still unclear. A postmortem analysis in MSA patients revealed α-syn within OPCs and an increased number of striatal OPCs. In an MSA mouse model, an age-dependent increase of dividing OPCs within the striatum and the cortex was detected. Despite of myelin loss, there was no reduction of mature oligodendrocytes in the corpus callosum or the striatum. Dissecting the underlying molecular mechanisms an oligodendroglial cell line expressing human α-syn revealed that α-syn delays OPC maturation by severely downregulating myelin-gene regulatory factor and myelin basic protein. Brain-derived neurotrophic factor was reduced in MSA models and its in vitro supplementation partially restored the phenotype. Taken together, efficacious induction of OPC maturation may open the window to restore glial and neuronal function in MSA.
Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Verena E L
VE
May
Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Benjamin
B
Ettle
Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Anne-Maria
AM
Poehler
Department of Neurosciences and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Silke
S
Nuber
Department of Neurosciences and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Kiren
K
Ubhi
Department of Neurosciences and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Edward
E
Rockenstein
Junior Research Group III, Interdisciplinary Centre of Clinical Research, Nikolaus Fiebiger Centre for Molecular Medicine, University Hospital Erlangen, Erlangen, Germany.
Beate
B
Winner
Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Michael
M
Wegner
Department of Neurosciences and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Eliezer
E
Masliah
Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department of Neurosciences and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address: juergen.winkler@uk-erlangen.de.
Jürgen
J
Winkler
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000473:pathology*; D009836:Oligodendroglia / Q000166:cytology* / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology* / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism / Q000502:physiology*
D051844:alpha-Synuclein
Alpha-synuclein; CG4; Differentiation; Multiple system atrophy; Myelin basic protein; Oligodendrocyte precursors; Oligodendrogenesis; Platelet derived growth factor receptor alpha; Transgenic; maturation