Oxidative Stress Promotes Uptake, Accumulation, and Oligomerization of Extracellular α-Synuclein in Oligodendrocytes

Abstract

The accumulation and aggregation of α-synuclein (α-Syn) in glial cytoplasmic inclusions originating in oligodendrocytes is a characteristic hallmark of multiple system atrophy, a progressive adult onset neurodegenerative disorder. The origin of α-Syn deposition in oligodendrocytes in multiple system atrophy is still unclear, but the uptake of α-Syn from the environment after neuronal secretion has been discussed. The present study was undertaken to investigate the consequences of α-Syn uptake from the environment in cultured oligodendroglial cells and its localization and potential to form intracellular aggregates in the absence or presence of the microtubule-associated protein tau, which has been demonstrated to act synergistically with α-Syn. Primary rat brain oligodendrocytes and clonal oligodendroglial OLN-93 cells were incubated with human recombinant soluble and pre-aggregated α-Syn. The data show that oligodendrocytes are capable to take up and internalize soluble and pre-aggregated α-Syn from their growth medium. In a time-dependent manner, α-Syn oligomerizes and small intracellular aggregates are formed. These do not exert cytotoxic responses or mitochondrial impairment. Oxidative stress exerted by hydrogen peroxide further promotes α-Syn oligomer formation and leads to an enlargement of the aggregates. This process is not affected or modified by the presence of tau in OLN-93 cells. Furthermore, membrane lipid modification by docosahexaenoic acid promotes α-Syn uptake and oligomerization, indicating that changing the membrane lipid composition and structure contributes to the protein aggregation process and pathological events. Hence, although α-Syn taken up by oligodendrocytes from the environment is not toxic per se, under conditions of oxidative stress, which might occur during chronic disease progression and aging, aggregates are enlarged and eventually may contribute to cytotoxicity and cellular death.

Higher levels of myelin phospholipids in brains of neuronal α-Synuclein transgenic mice precede myelin loss

“…Moreover, α-Syn uptake does not exert cytotoxic effects per se , yet, under stress conditions, for example, oxidative stress, larger α-Syn aggregates are formed which may eventually contribute to cytotoxicity and cell death [33, 52]. Here we tested whether α-Syn uptake affects oligodendrocyte maturation and myelin-like membrane formation in vitro .…”

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…). Interestingly, oxidative stress has been reported to increase both the uptake and oligomerization of α‐Syn in extracellular treatment models (Pukass and Richter‐Landsberg ). Antioxidants, such as curcumin (Wang et al .…”

Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?

“…In line, by enhancing oxidative modifications of alpha-synuclein using the mitochondrial inhibitor 3-nitropropionic acid (3NP), neuropathology and neurological deficits exacerbated in both the PLP- and the MBP-driven transgenic MSA model implying increased susceptibility of alpha-synuclein-bearing OLGs toward oxidative stress [187, 197]. In cultured OLGs, alpha-synuclein aggregation was promoted under oxidative conditions, while increased intracellular alpha-synuclein per se exerted no toxic effect [198–201]. In line, OLG overexpressing alpha-synuclein only underwent apoptosis when co-expression of p25-alpha triggered alpha-synuclein aggregation [202, 203].…”

“…Oligodendrocyte progenitor cells (OPCs)System/tissueReference Alpha-synuclein accumulation in OPCsHuman: postmortem[183] Increased numbers of OPCsHuman: postmortem[182, 183]In vivo: MBP model[183] Impaired maturation of alpha-synuclein-expressing OPCsIn vitro: primary and permanent cells[174, 183]B. Oligodendrocytes (OLGs)System/tissueReference GCIsHuman: postmortem[66, 108, 116]  Alpha-synuclein as major GCI componentHuman: postmortem[126–128, 152]  Modification and insolubility of alpha-synucleinHuman: postmortem[159–163]  Correlation between GCIs distribution and neurodegenerationHuman: postmortem[104, 122–125] Moderate loss of OLGsHuman: postmortem[117]In vivo: CNP and PLP models[184, 193, 195] Increased activity of unfolded protein responseHuman: postmortem[157] Altered morphology of oligodendroglial nucleiHuman: postmortem[158] Autophagic and proteasomal dysfunctionIn vitro: primary cells[196] Increased vulnerability toward proteolytic stressIn vivo: PLP model[195] Increased vulnerability toward oxidative stressIn vivo: MBP and PLP models[192, 197, 204–206]In vitro: primary and permanent cells[198–201] Reduced neurotrophic supportIn vivo: MBP model[208, 209]C. MyelinSystem/tissueReference Myelin loss…”