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

Abstract

SummaryGlial 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.

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…Drosophila serves as a powerful model organism for investigating human neurodegeneration in large part due to the high conservation of disease‐related genes (McGurk, Berson, & Bonini, ; Rubin et al, ). To explore the relevance of our differentially expressed genes, we identified their rat, mouse, and human orthologs and cross‐referenced this list with additional publicly available lists of differentially expressed genes identified in transcriptomic studies of MSA animal models (Kaji et al, ; Schafferer et al, ) or human post‐mortem MSA brains (Langerveld, Mihalko, DeLong, Walburn, & Ide, ; Mills, Ward, Kim, Halliday, & Janitz, ). We also compared the ortholog list to genes that have been identified as candidate risk genes for any human α‐synucleinopathy by examining genome‐wide association or whole exome sequencing studies from MSA (X. Gu et al, ; Sailer et al, ), PD (Chang et al, ; Guo et al, ; Jansen et al, ; Li et al, ; Quadri et al, ; Robak et al, ; Sandor et al, ; Schormair et al, ; Shulskaya et al, ; Siitonen et al, ; Ylönen et al, ), or DLB (Guerreiro et al, ; Keogh et al, ; Peuralinna et al, ).…”

Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines

“…While NG2 cells were initially thought to only give rise to oligodendrocytes [3,16,32,45,48], it is now known they can also differentiate into astrocytes [10,47,48]. Recently, two groups reported co-localization of α-synuclein neuropathology with NG2 cells in MSA patient samples [15,24]. Using immunofluorescence with an NG2-specific antibody to determine co-localization with αsynuclein, we found that neither Tg mouse model developed α-synuclein inclusions in NG2 cells (Online Resource, Fig.…”

Experimental models of prion‐like protein propagation

“…20 Kaji et al reported that GCI-like accumulations are more likely to appear in progenitor cells than mature oligodendrocytes, using cultured cells as a model. 21 Uemura et al reported accumulation of α-synuclein in oligodendrocytes of aged mice inoculated with recombinant α-synuclein fibrils. 22 However, in most cases of MSA, GCIs are the main pathology, and neuronal inclusions are rarely observed.…”