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

Publication date: Available online 11 January 2018 Source:Stem Cell Reports Author(s): 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 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 syste...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research