Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage
Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage
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DOI：
10.1016/j.mcn.2017.04.009
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发表时间：
2017-07-01
影响因子：
3.5
通讯作者：
Erlandsson, Anna
中科院分区：
文献类型：
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作者：
Lindstrom, Veronica;Gustafsson, Gabriel;Erlandsson, Anna
主要由聚集的α-突触核蛋白组成的路易体的存在是帕金森病（PD）和路易体痴呆（DLB）的病理学标志。α-突触核蛋白包涵体主要存在于神经元中，但也经常出现在星形胶质细胞中。然而，星形胶质细胞中α-突触核蛋白包涵体的病理学意义和胶质细胞清除有毒α-突触核蛋白种类的能力仍然未知。在本研究中，我们研究了在原代神经元，星形胶质细胞和少突胶质细胞的共培养系统的摄取，降解和毒性作用的寡聚α-突触核蛋白。发现α-突触核蛋白寡聚体与神经胶质细胞共定位，并且发现星形胶质细胞内化特别大量的蛋白质。摄取后，星形胶质细胞开始通过溶酶体途径降解低聚物，但由于消化不完全，大量的细胞内沉积物仍然存在。此外，星形胶质细胞显示线粒体异常。总之，我们的数据表明，星形胶质细胞在清除细胞外空间的有毒α-突触核蛋白物种中发挥重要作用。然而，当它们的降解能力负担过重时，α-突触核蛋白沉积物可以持续存在并导致有害的细胞过程。(C)2017爱思唯尔公司All rights reserved.
The presence of Lewy bodies, mainly consisting of aggregated a-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The alpha-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of alpha-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic alpha-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric alpha-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes. Alpha-synuclein oligomers were found to co-localize with the glial cells and the astrocytes were found to internalize particularly large amounts of the protein. Following ingestion, the astrocytes started to degrade the oligomers via the lysosomal pathway but, due to incomplete digestion, large intracellular deposits remained. Moreover, the astrocytes displayed mitochondrial abnormalities. Taken together, our data indicate that astrocytes play an important role in the clearance of toxic alpha-synuclein species from the extracellular space. However, when their degrading capacity is overburdened, alpha-synuclein deposits can persist and result in detrimental cellular processes. (C) 2017 Elsevier Inc. All rights reserved.