Alpha-Synuclein Expression in the Oligodendrocyte Lineage: an In Vitro and In Vivo Study Using Rodent and Human Models

Abstract

SummaryIn this study, we sought evidence for alpha-synuclein (ASYN) expression in oligodendrocytes, as a possible endogenous source of ASYN to explain its presence in glial inclusions found in multiple system atrophy (MSA) and Parkinson’s disease (PD). We identified ASYN in oligodendrocyte lineage progenitors isolated from the rodent brain, in oligodendrocytes generated from embryonic stem cells, and in induced pluripotent stem cells produced from fibroblasts of a healthy individual and patients diagnosed with MSA or PD, in cultures in vitro. Notably, we observed a significant decrease in ΑSYN during oligodendrocyte maturation. Additionally, we show the presence of transcripts in PDGFRΑ/CD140a+ cells and SOX10+ oligodendrocyte lineage nuclei isolated by FACS from rodent and human healthy and diseased brains, respectively. Our work identifies ASYN in oligodendrocyte lineage cells, and it offers additional in vitro cellular models that should provide significant insights of the functional implication of ASYN during oligodendrocyte development and disease.

Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy

“…Although not statistically significant, SNCA mRNA level may be increased in MSA compared with control brains 86. Subsequently, Djelloul and colleagues identified SNCA transcripts in oligodendrocyte lineage cells, including embryonic stem cell and induced pluripotent stem cell-derived oligodendrocytes from patients with MSA 81. This finding is in line with those of Asi’s study, but it remains to be determined whether the SNCA transcripts identified are reminiscent of basal expression in quiescent oligodendrocyte precursor cells.…”

“…This finding is in line with those of Asi’s study, but it remains to be determined whether the SNCA transcripts identified are reminiscent of basal expression in quiescent oligodendrocyte precursor cells. Furthermore, α-synuclein expression decreased during oligodendrocyte maturation 81. Taken together, SNCA transcripts identified in oligodendrocyte lineage cells may not be the origin of α-synuclein in GCIs in MSA.…”

“…In MSA brains, relocation of p25α from the myelin sheath and nucleus to the cytoplasm has been considered to precede aggregation of α-synuclein78–80; however, the cellular origin of α-synuclein is controversial. α-Synuclein is a neuronal protein that localises predominantly to presynaptic terminals 81. Even though accumulation of α-synuclein in oligodendrocytes is the pathological hallmark in MSA, SNCA mRNA was not expressed in oligodendrocytes in MSA or control brains 82 83.…”

The neuropathology of multiple system atrophy and its therapeutic implications

“…Another option is that a dysfunction in the clearance machinery is a prerequisite for α-syn uptake and/or accumulation in oligodendrocytes. In both scenarios, the oligodendroglial accumulation of α-syn may be further potentiated by increased expression of its gene (Asi et al, 2014; Djelloul et al, 2015) and oligo-dendrocyte-to-oligodendrocyte propagation. Finally, other suggested mechanisms are the involvement of altered iron metabolism in oligo-dendrocytes (Visanji et al, 2013), and epigenetic and/or environmental factors (Sturm et al, 2016).…”

Potential Modes of Intercellular Alpha-Synuclein Transmission

“…GCIs have a triangular or sickle-like morphology (Miki et al, 2010;Grazia Spillantini et al, 1998) and occur predominantly in oligodendrocytes (Ahmed et al, 2012). Although oligodendrocyte lineages are known to express α-syn mRNA at low levels both normally and in MSA, α-syn is expressed primarily in neurons, implicating uptake as the main source of α-syn in GCIs (Asi et al, 2014;Djelloul et al, 2015).…”