Brudek Tomasz, Winge Kristian, Rasmussen Nadja Bredo, Bahl Justyna Maria Czarna, Tanassi Julia, Agander Tina Klitmøller, Hyde Thomas M, Pakkenberg Bente
Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen NV, Denmark.
Bispebjerg Movement Disorders Biobank, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen N, Denmark.
J Neurochem. 2016 Jan;136(1):172-85. doi: 10.1111/jnc.13392. Epub 2015 Nov 11.
Together with Parkinson's disease (PD) and dementia with Lewy bodies, multiple system atrophy (MSA) is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies. Previously, it has been shown that α-synuclein, parkin, and synphilin-1 display disease-specific transcription patterns in frontal cortex in PD, dementia with Lewy bodies, and MSA, and thus may mediate the development of α-synucleinopathies. In this study, the differential expression of α-synuclein isoforms on transcriptional and translational levels was ascertained in MSA patients in comparison with PD cases and normal controls using isoform-specific primers and exon-specific antibodies in substantia nigra, striatum, cerebellar cortex, and nucleus dentatus. These regions are severely affected by α-synuclein pathology and neurodegeneration. Furthermore, we have also investigated transcript levels for parkin and synphilin-1 isoforms. In MSA brains, α-synuclein140 and α-synuclein 112 isoform levels were significantly increased, whereas levels of the α-synuclein 126 isoform were decreased in the substantia nigra, striatum, cerebellar cortex, and nucleus dentatus versus controls. Moreover, in MSA cases, we showed increased levels of parkin isoforms lacking the N-terminal ubiquitin-like domain and an aggregation-prone synphilin-1A isoform that causes neuronal toxicity in MSA. In PD brains, parkin transcript variant 3, 7, and 11 were significantly and specifically over-expressed in the striatum and cerebellar cortex, together with synphilin-1A and 1C. The changes of isoform expression profiles in neurodegenerative diseases suggest alterations in the regulation of transcription and/or splicing events, leading to regional/cellular events that may be important for the highly increased aggregation of α-synuclein in the brain. We report differential expression of α-synuclein, parkin, and synphilin-1 isoforms in multiple system atrophy (MSA) versus Parkinson's disease and normal control brains. We have focused on brain regions that are severely affected by α-synuclein pathology and neurodegeneration in MSA. The reported changes of isoform expression profiles suggest alterations in the regulation of transcription that may be important for aggregation of α-synuclein in the brain.
多系统萎缩（MSA）与帕金森病（PD）和路易体痴呆一样，是一组被称为α-突触核蛋白病的多种神经退行性疾病中的一员。此前已有研究表明，α-突触核蛋白、帕金蛋白和突触核蛋白-1在PD、路易体痴呆和MSA的额叶皮质中呈现疾病特异性转录模式，因此可能介导α-突触核蛋白病的发展。在本研究中，使用异构体特异性引物和外显子特异性抗体，在黑质、纹状体、小脑皮质和齿状核中，与PD病例和正常对照相比，确定了MSA患者中α-突触核蛋白异构体在转录和翻译水平上的差异表达。这些区域受到α-突触核蛋白病理和神经退行性变的严重影响。此外，我们还研究了帕金蛋白和突触核蛋白-1异构体的转录水平。在MSA脑内，与对照组相比，黑质、纹状体、小脑皮质和齿状核中α-突触核蛋白140和α-突触核蛋白112异构体水平显著升高，而α-突触核蛋白126异构体水平降低。此外，在MSA病例中，我们发现缺乏N端泛素样结构域的帕金蛋白异构体水平升高，以及一种在MSA中导致神经元毒性的易于聚集的突触核蛋白-1A异构体水平升高。在PD脑内，帕金转录变体3、7和11在纹状体和小脑皮质中显著且特异性地过度表达，同时突触核蛋白-1A和1C也过度表达。神经退行性疾病中异构体表达谱的变化表明转录和/或剪接事件的调控发生改变，导致区域/细胞事件，这可能对大脑中α-突触核蛋白的高度聚集很重要。我们报告了多系统萎缩（MSA）与帕金森病和正常对照脑相比，α-突触核蛋白、帕金蛋白和突触核蛋白-1异构体的差异表达。我们专注于MSA中受α-突触核蛋白病理和神经退行性变严重影响的脑区。所报道的异构体表达谱变化表明转录调控的改变可能对大脑中α-突触核蛋白的聚集很重要。
