Poul Henning Jensen

Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models

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  • Panagiota Mavroeidi, Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, 11527, Athens, Greece.
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  • Fedra Arvanitaki, Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, 11527, Athens, Greece.
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  • Anastasia-Kiriaki Karakitsou, Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, 11527, Athens, Greece.
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  • Maria Vetsi, Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, 11527, Athens, Greece.
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  • Ismini Kloukina, Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
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  • Markus Zweckstetter, Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany.
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  • Karin Giller, Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany.
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  • Stefan Becker, Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany.
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  • Zachary A Sorrentino, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA.
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  • Benoit I Giasson, McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.
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  • Poul Henning Jensen
  • Leonidas Stefanis, 1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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  • Maria Xilouri, Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, 11527, Athens, Greece. mxilouri@bioacademy.gr.

Multiple system atrophy (MSA) is characterized by the presence of distinctive glial cytoplasmic inclusions (GCIs) within oligodendrocytes that contain the neuronal protein alpha-synuclein (aSyn) and the oligodendroglia-specific phosphoprotein TPPP/p25α. However, the role of oligodendroglial aSyn and p25α in the formation of aSyn-rich GCIs remains unclear. To address this conundrum, we have applied human aSyn (haSyn) pre-formed fibrils (PFFs) to rat wild-type (WT)-, haSyn-, or p25α-overexpressing oligodendroglial cells and to primary differentiated oligodendrocytes derived from WT, knockout (KO)-aSyn, and PLP-haSyn-transgenic mice. HaSyn PFFs are readily taken up by oligodendroglial cells and can recruit minute amounts of endogenous aSyn into the formation of insoluble, highly aggregated, pathological assemblies. The overexpression of haSyn or p25α accelerates the recruitment of endogenous protein and the generation of such aberrant species. In haSyn PFF-treated primary oligodendrocytes, the microtubule and myelin networks are disrupted, thus recapitulating a pathological hallmark of MSA, in a manner totally dependent upon the seeding of endogenous aSyn. Furthermore, using oligodendroglial and primary cortical cultures, we demonstrated that pathology-related S129 aSyn phosphorylation depends on aSyn and p25α protein load and may involve different aSyn "strains" present in oligodendroglial and neuronal synucleinopathies. Importantly, this hypothesis was further supported by data obtained from human post-mortem brain material derived from patients with MSA and dementia with Lewy bodies. Finally, delivery of haSyn PFFs into the mouse brain led to the formation of aberrant aSyn forms, including the endogenous protein, within oligodendroglia and evoked myelin decompaction in WT mice, but not in KO-aSyn mice. This line of research highlights the role of endogenous aSyn and p25α in the formation of pathological aSyn assemblies in oligodendrocytes and provides in vivo evidence of the contribution of oligodendroglial aSyn in the establishment of aSyn pathology in MSA.

Original languageEnglish
JournalActa Neuropathologica
Volume138
Issue3
Pages (from-to)415-441
Number of pages27
ISSN0001-6322
DOIs
Publication statusPublished - Sep 2019

    Research areas

  • Alpha-synuclein, Multiple system atrophy, Myelin, Oligodendrocytes, Seeding, Tubulin polymerization promoting protein

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