Department of Biology, Molecular Neurobiology, University of Oldenburg, 26111, Oldenburg, Germany.
J Mol Neurosci. 2014 Mar;52(3):339-52. doi: 10.1007/s12031-013-0154-x. Epub 2013 Nov 12.
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.
α-突触核蛋白（α-Syn）在源自少突胶质细胞的神经胶质细胞质包含物中的积累和聚集是多系统萎缩的特征性标志，多系统萎缩是一种进行性成人发病的神经退行性疾病。多系统萎缩中少突胶质细胞中 α-Syn 沉积的起源尚不清楚，但已经讨论了神经元分泌后从环境中摄取 α-Syn。本研究旨在探讨在培养的少突胶质细胞中从环境中摄取 α-Syn 的后果，以及在不存在或存在微管相关蛋白 tau 的情况下，其在细胞内聚集的定位和潜力，tau 已被证明与 α-Syn 协同作用。原代大鼠脑少突胶质细胞和克隆少突胶质细胞 OLN-93 细胞用重组人可溶性和预聚集的 α-Syn 孵育。数据表明，少突胶质细胞能够从其生长培养基中摄取和内化可溶性和预聚集的 α-Syn。以时间依赖性方式，α-Syn 寡聚化并形成小的细胞内聚集体。这些不会引起细胞毒性反应或线粒体损伤。过氧化氢施加的氧化应激进一步促进 α-Syn 寡聚体形成，并导致聚集体的扩大。这一过程不受 OLN-93 细胞中 tau 的存在的影响或改变。此外，二十二碳六烯酸对膜脂质的修饰促进了 α-Syn 的摄取和寡聚化，表明改变膜脂质组成和结构有助于蛋白质聚集过程和病理事件。因此，尽管少突胶质细胞从环境中摄取的 α-Syn 本身并不有毒，但在慢性疾病进展和衰老期间可能发生的氧化应激条件下，聚集体会扩大，最终可能导致细胞毒性和细胞死亡。
