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

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.

• Authors: 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
• Journal: Stem cell reports (Stem Cell Reports) Vol. 10 Issue 2 Pg. 356-365 (02 13 2018) ISSN: 2213-6711 [Electronic] United States
• PMID: 29337114 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• alpha-Synuclein

Topics

• Animals
• Brain (metabolism, pathology)
• Cell Culture Techniques
• Cell Differentiation (genetics)
• Humans
• Inclusion Bodies (genetics, pathology)
• Multiple System Atrophy (genetics, metabolism, pathology)
• Neuroglia (metabolism, pathology)
• Neurons (metabolism, pathology)
• Oligodendrocyte Precursor Cells (metabolism, pathology)
• Oligodendroglia (metabolism)
• Rats
• alpha-Synuclein (genetics, metabolism)