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 L. Dawson, Ted M. Dawson, Ryosuke Takahashi

Research output: Contribution to journalArticlepeer-review

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)
Pages (from-to)356-365
Number of pages10
JournalStem Cell Reports
Volume10
Issue number2
DOIs
StatePublished - Feb 13 2018

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

Fingerprint Dive into the research topics of 'Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy'. Together they form a unique fingerprint.

Cite this