Poul Henning Jensen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. / Mavroeidi, Panagiota; Arvanitaki, Fedra; Karakitsou, Anastasia-Kiriaki; Vetsi, Maria; Kloukina, Ismini; Zweckstetter, Markus; Giller, Karin; Becker, Stefan; Sorrentino, Zachary A; Giasson, Benoit I; Jensen, Poul Henning; Stefanis, Leonidas; Xilouri, Maria.

In: Acta Neuropathologica, Vol. 138, No. 3, 09.2019, p. 415-441.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Mavroeidi, P, Arvanitaki, F, Karakitsou, A-K, Vetsi, M, Kloukina, I, Zweckstetter, M, Giller, K, Becker, S, Sorrentino, ZA, Giasson, BI, Jensen, PH, Stefanis, L & Xilouri, M 2019, 'Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models', Acta Neuropathologica, vol. 138, no. 3, pp. 415-441. https://doi.org/10.1007/s00401-019-02014-y

APA

Mavroeidi, P., Arvanitaki, F., Karakitsou, A-K., Vetsi, M., Kloukina, I., Zweckstetter, M., ... Xilouri, M. (2019). Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. Acta Neuropathologica, 138(3), 415-441. https://doi.org/10.1007/s00401-019-02014-y

CBE

Mavroeidi P, Arvanitaki F, Karakitsou A-K, Vetsi M, Kloukina I, Zweckstetter M, Giller K, Becker S, Sorrentino ZA, Giasson BI, Jensen PH, Stefanis L, Xilouri M. 2019. Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. Acta Neuropathologica. 138(3):415-441. https://doi.org/10.1007/s00401-019-02014-y

MLA

Vancouver

Mavroeidi P, Arvanitaki F, Karakitsou A-K, Vetsi M, Kloukina I, Zweckstetter M et al. Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. Acta Neuropathologica. 2019 Sep;138(3):415-441. https://doi.org/10.1007/s00401-019-02014-y

Author

Mavroeidi, Panagiota ; Arvanitaki, Fedra ; Karakitsou, Anastasia-Kiriaki ; Vetsi, Maria ; Kloukina, Ismini ; Zweckstetter, Markus ; Giller, Karin ; Becker, Stefan ; Sorrentino, Zachary A ; Giasson, Benoit I ; Jensen, Poul Henning ; Stefanis, Leonidas ; Xilouri, Maria. / Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. In: Acta Neuropathologica. 2019 ; Vol. 138, No. 3. pp. 415-441.

Bibtex

@article{63d6971bc08e4c2ba20054d165bf604e,
title = "Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models",
abstract = "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.",
keywords = "Alpha-synuclein, Multiple system atrophy, Myelin, Oligodendrocytes, Seeding, Tubulin polymerization promoting protein",
author = "Panagiota Mavroeidi and Fedra Arvanitaki and Anastasia-Kiriaki Karakitsou and Maria Vetsi and Ismini Kloukina and Markus Zweckstetter and Karin Giller and Stefan Becker and Sorrentino, {Zachary A} and Giasson, {Benoit I} and Jensen, {Poul Henning} and Leonidas Stefanis and Maria Xilouri",
year = "2019",
month = "9",
doi = "10.1007/s00401-019-02014-y",
language = "English",
volume = "138",
pages = "415--441",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer",
number = "3",

}

RIS

TY - JOUR

T1 - Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models

AU - Mavroeidi, Panagiota

AU - Arvanitaki, Fedra

AU - Karakitsou, Anastasia-Kiriaki

AU - Vetsi, Maria

AU - Kloukina, Ismini

AU - Zweckstetter, Markus

AU - Giller, Karin

AU - Becker, Stefan

AU - Sorrentino, Zachary A

AU - Giasson, Benoit I

AU - Jensen, Poul Henning

AU - Stefanis, Leonidas

AU - Xilouri, Maria

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

KW - Alpha-synuclein

KW - Multiple system atrophy

KW - Myelin

KW - Oligodendrocytes

KW - Seeding

KW - Tubulin polymerization promoting protein

U2 - 10.1007/s00401-019-02014-y

DO - 10.1007/s00401-019-02014-y

M3 - Journal article

C2 - 31011860

VL - 138

SP - 415

EP - 441

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 3

ER -