Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy

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 Dawson, Ted M Dawson, Ryosuke Takahashi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalStem Cell Reports
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Synucleins
Multiple System Atrophy
Oligodendroglia
Inclusion Bodies
Neuroglia
Proteolysis
Cell culture
Rats
Brain
RNA
Primary Cell Culture
Myelin Sheath
Proteins

Keywords

  • Autophagy
  • Glial cytoplasmic inclusion
  • Misfolding
  • Multiple system atrophy
  • Neurotrophic factor
  • Oligodendrocyte precursor cells
  • Oligodendrocytes
  • Primary cell culture
  • Synucleinopathy
  • α-synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy. / Kaji, Seiji; Maki, Takakuni; Kinoshita, Hisanori; Uemura, Norihito; Ayaki, Takashi; Kawamoto, Yasuhiro; Furuta, Takahiro; Urushitani, Makoto; Hasegawa, Masato; Kinoshita, Yusuke; Ono, Yuichi; Mao, Xiaobo; Quach, Tran H.; Iwai, Kazuhiro; Dawson, Valina; Dawson, Ted M; Takahashi, Ryosuke.

In: Stem Cell Reports, 01.01.2018.

Research output: Contribution to journalArticle

Kaji, S, Maki, T, Kinoshita, H, Uemura, N, Ayaki, T, Kawamoto, Y, Furuta, T, Urushitani, M, Hasegawa, M, Kinoshita, Y, Ono, Y, Mao, X, Quach, TH, Iwai, K, Dawson, V, Dawson, TM & Takahashi, R 2018, 'Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy', Stem Cell Reports. https://doi.org/10.1016/j.stemcr.2017.12.001
Kaji, Seiji ; Maki, Takakuni ; Kinoshita, Hisanori ; Uemura, Norihito ; Ayaki, Takashi ; Kawamoto, Yasuhiro ; Furuta, Takahiro ; Urushitani, Makoto ; Hasegawa, Masato ; Kinoshita, Yusuke ; Ono, Yuichi ; Mao, Xiaobo ; Quach, Tran H. ; Iwai, Kazuhiro ; Dawson, Valina ; Dawson, Ted M ; Takahashi, Ryosuke. / Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy. In: Stem Cell Reports. 2018.
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abstract = "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.",
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AU - Maki, Takakuni

AU - Kinoshita, Hisanori

AU - Uemura, Norihito

AU - Ayaki, Takashi

AU - Kawamoto, Yasuhiro

AU - Furuta, Takahiro

AU - Urushitani, Makoto

AU - Hasegawa, Masato

AU - Kinoshita, Yusuke

AU - Ono, Yuichi

AU - Mao, Xiaobo

AU - Quach, Tran H.

AU - Iwai, Kazuhiro

AU - Dawson, Valina

AU - Dawson, Ted M

AU - Takahashi, Ryosuke

PY - 2018/1/1

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N2 - 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.

AB - 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.

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