Low levels of astroglial markers in Parkinson's disease: relationship to α-synuclein accumulation.
Low levels of astroglial markers in Parkinson's disease: relationship to α-synuclein accumulation.
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DOI：
10.1016/j.nbd.2015.06.010
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发表时间：
2015-10
影响因子：
6.1
通讯作者：
Kish SJ
中科院分区：
文献类型：
--
作者：
Tong J;Ang LC;Williams B;Furukawa Y;Fitzmaurice P;Guttman M;Boileau I;Hornykiewicz O;Kish SJ
虽然脑胶质细胞增多症是脑损伤的正常反应，但关于帕金森氏病(PD)黑质退行性变的星形胶质细胞增多症的程度的报道是相互矛盾的。最近也有研究表明，这种疾病中黑质α-突触核蛋白的积聚可能会抑制星形胶质细胞的激活，进而可能加剧退变过程。这项研究检测了帕金森病患者和多系统萎缩和进行性核上性麻痹患者的脑内星形胶质细胞标记物的蛋白水平(完整的蛋白、碎片和聚集体，如果有的话)及其与α-突触核蛋白的关系。用定量免疫印迹法检测PD(n=10)、MSA(n=11)、PSP(n=11)和正常对照组(n=10)脑组织中星形胶质细胞标志物胶质纤维酸性蛋白(GFAP)、波形蛋白和热休克蛋白-27(Hsp27)的表达。正如预期的那样，MSA(壳核和黑质；尾状和GT；额叶皮质)和PSP(黑质和尾状；壳核，额叶皮质)都显示出广泛但区域性的标记物免疫反应增强的模式，特别是对于部分蛋白分解片段(所有三种)和聚集体(GFAP)。相反，在帕金森病患者中，除了黑质和额叶皮质中裂解的波形蛋白水平有不同程度升高的趋势外，这三种标记物的免疫反应在帕金森病患者中基本正常。在帕金森病患者中，黑质胶质纤维酸性蛋白水平与α-突触核蛋白积聚呈负相关，而MSA则相反。我们的生化结果显示帕金森病黑质星形胶质细胞标记物的蛋白水平基本正常，并与α-突触核蛋白浓度呈负相关，这与最近一些神经病理学报道的轻度星形胶质细胞反应一致，并与推测α-突触核蛋白过度积聚可能抑制这种疾病的星形胶质细胞增生相一致。如果星形胶质细胞增生症在一定程度上保护变性的黑质免受损害，旨在使帕金森病患者星形胶质细胞反应正常化的治疗方法可能会有所帮助。
Although gliosis is a normal response to brain injury, reports on the extent of astrogliosis in the degenerating substantia nigra in Parkinson's disease (PD) are conflicting. It has also been recently suggested that accumulation of nigral α-synuclein in this disorder might suppress astrocyte activation which in turn could exacerbate the degenerative process. This study examined brain protein levels (intact protein, fragments, and aggregates, if any) of astroglial markers and their relationship to α-synuclein in PD and in the positive control parkinson-plus conditions multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Autopsied brain homogenates of patients with PD (n=10), MSA (n=11), PSP (n=11) and matched controls (n=10) were examined for the astroglial markers glial fibrillary acidic protein (GFAP), vimentin, and heat shock protein-27 (Hsp27) by quantitative immunoblotting. As expected, both MSA (putamen > substantia nigra > caudate > frontal cortex) and PSP (substantia nigra > caudate > putamen, frontal cortex) showed widespread but regionally specific pattern of increased immunoreactivity of the markers, in particular for the partially proteolyzed fragments (all three) and aggregates (GFAP). In contrast, immunoreactivity of the three markers was largely normal in PD in brain regions examined with the exception of trends for variably increased levels of cleaved vimentin in substantia nigra and frontal cortex. In patients with PD, GFAP levels in the substantia nigra correlated inversely with α-synuclein accumulation whereas the opposite was true for MSA. Our biochemical findings of generally normal protein levels of astroglial markers in substantia nigra of PD, and negative correlation with α-synuclein concentration, are consistent with some recent neuropathology reports of mild astroglial response and with the speculation that astrogliosis might be suppressed in this disorder by excessive α-synuclein accumulation. Should astrogliosis protect, to some extent, the degenerating substantia nigra from damage, therapeutics aimed at normalization of astrocyte reaction in PD could be helpful.