Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy
Summary: Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenous α-syn expression in oligodend...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-02-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671117305301 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Seiji Kaji Takakuni Maki Hisanori Kinoshita Norihito Uemura Takashi Ayaki Yasuhiro Kawamoto Takahiro Furuta Makoto Urushitani Masato Hasegawa Yusuke Kinoshita Yuichi Ono Xiaobo Mao Tran H. Quach Kazuhiro Iwai Valina L. Dawson Ted M. Dawson Ryosuke Takahashi |
| spellingShingle |
Seiji Kaji Takakuni Maki Hisanori Kinoshita Norihito Uemura Takashi Ayaki Yasuhiro Kawamoto Takahiro Furuta Makoto Urushitani Masato Hasegawa Yusuke Kinoshita Yuichi Ono Xiaobo Mao Tran H. Quach Kazuhiro Iwai Valina L. Dawson Ted M. Dawson Ryosuke Takahashi Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy Stem Cell Reports |
| author_facet |
Seiji Kaji Takakuni Maki Hisanori Kinoshita Norihito Uemura Takashi Ayaki Yasuhiro Kawamoto Takahiro Furuta Makoto Urushitani Masato Hasegawa Yusuke Kinoshita Yuichi Ono Xiaobo Mao Tran H. Quach Kazuhiro Iwai Valina L. Dawson Ted M. Dawson Ryosuke Takahashi |
| author_sort |
Seiji Kaji |
| title |
Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy |
| title_short |
Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy |
| title_full |
Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy |
| title_fullStr |
Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy |
| title_full_unstemmed |
Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy |
| title_sort |
pathological endogenous α-synuclein accumulation in oligodendrocyte precursor cells potentially induces inclusions in multiple system atrophy |
| publisher |
Elsevier |
| series |
Stem Cell Reports |
| issn |
2213-6711 |
| publishDate |
2018-02-01 |
| description |
Summary: Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenous α-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains. : In this article, Maki and Takahashi report that the internalization of exogenous α-synuclein fibrils in oligodendrocyte precursor cells triggers misfolding and accumulation of endogenous α-synuclein via seeding mechanisms, which may eventually lead to neurodegeneration and myelin disruption in multiple system atrophy by compromising the oligodendroglial function of neuronal support and myelination. Keywords: α-synuclein, oligodendrocytes, oligodendrocyte precursor cells, primary cell culture, multiple system atrophy, synucleinopathy, glial cytoplasmic inclusion, neurotrophic factor, misfolding, autophagy |
| url |
http://www.sciencedirect.com/science/article/pii/S2213671117305301 |
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1725593714582093824 |
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doaj-bed96d5567674d73b17dcc007f16421b2020-11-24T23:14:33ZengElsevierStem Cell Reports2213-67112018-02-01102356365Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System AtrophySeiji Kaji0Takakuni Maki1Hisanori Kinoshita2Norihito Uemura3Takashi Ayaki4Yasuhiro Kawamoto5Takahiro Furuta6Makoto Urushitani7Masato Hasegawa8Yusuke Kinoshita9Yuichi Ono10Xiaobo Mao11Tran H. Quach12Kazuhiro Iwai13Valina L. Dawson14Ted M. Dawson15Ryosuke Takahashi16Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, Japan; Corresponding authorDepartment of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, JapanDepartment of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, Japan; Department of Neurology, Rakusai Shimizu Hospital, Nishikyo-ku, 610-1106 Kyoto, JapanDepartment of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto, JapanDepartment of Neurology, Shiga University of Medical Science, Otsu, 520-2192 Shiga, JapanDepartment of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, 156-8506 Tokyo, JapanDepartment of Developmental Neurobiology, KAN Research Institute, Inc., Kobe, 650-0047 Hyogo, JapanDepartment of Developmental Neurobiology, KAN Research Institute, Inc., Kobe, 650-0047 Hyogo, JapanNeuroregeneration and Stem Cell Program, Institute for Cell Engineering and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USANeuroregeneration and Stem Cell Program, Institute for Cell Engineering and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, JapanNeuroregeneration and Stem Cell Program, Institute for Cell Engineering and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USANeuroregeneration and Stem Cell Program, Institute for Cell Engineering and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USADepartment of Neurology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, 606-8397 Kyoto, Japan; Corresponding authorSummary: Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenous α-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains. : In this article, Maki and Takahashi report that the internalization of exogenous α-synuclein fibrils in oligodendrocyte precursor cells triggers misfolding and accumulation of endogenous α-synuclein via seeding mechanisms, which may eventually lead to neurodegeneration and myelin disruption in multiple system atrophy by compromising the oligodendroglial function of neuronal support and myelination. Keywords: α-synuclein, oligodendrocytes, oligodendrocyte precursor cells, primary cell culture, multiple system atrophy, synucleinopathy, glial cytoplasmic inclusion, neurotrophic factor, misfolding, autophagyhttp://www.sciencedirect.com/science/article/pii/S2213671117305301 |