Mills J D, Ward M, Kim W S, Halliday G M, Janitz M
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Neuroscience Research Australia, Sydney, NSW 2031, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Neuroscience. 2016 May 13;322:234-50. doi: 10.1016/j.neuroscience.2016.02.042. Epub 2016 Feb 24.
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease. The major pathological hallmark of MSA is the accumulation of α-synuclein in oligodendrocytes. In contrast to Parkinson's disease no definitive familial etiology for MSA has been determined. Yet, there is a growing body of evidence that perturbation of transcriptional processes leads to MSA pathology. Here we present the results of the first ribosomal-depleted strand-specific RNA-sequencing profile of the MSA brain frontal cortex tissue. Among the 123 differentially expressed genes over 50% were categorized as putative long intervening non-coding RNAs (lincRNAs). Along with the dysregulation of the non-coding portion of the transcriptome, the expression of protein coding genes was also affected, including serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 (SERPINA3), interleukin 1 receptor-like 1 (IL1RL1) and hemoglobin, beta (HBB). Also of interest was the alternative splicing of SNCA, along with the presence of an antisense transcript overlapping the 3' exon of SNCA. Moreover, we demonstrate widespread antisense transcription throughout the frontal cortex that is largely not affected by MSA-specific neurodegenerative process. MSA causes a large disruption of lincRNAs in the human brain along with protein coding genes related to iron metabolism and immune response regulation. Most of the lincRNAs specific for MSA were novel. Hence our study uncovers another level of complexity in transcriptional pathology of MSA.
多系统萎缩（MSA）是一种散发性神经退行性疾病。MSA的主要病理标志是α-突触核蛋白在少突胶质细胞中的积累。与帕金森病不同，MSA尚未确定明确的家族病因。然而，越来越多的证据表明转录过程的紊乱会导致MSA病理。在此，我们展示了MSA脑额叶皮质组织首次进行的核糖体缺失链特异性RNA测序分析结果。在123个差异表达基因中，超过50%被归类为假定的长链非编码RNA（lincRNA）。除了转录组非编码部分的失调外，蛋白质编码基因的表达也受到影响，包括丝氨酸蛋白酶抑制剂A家族（α-1抗蛋白酶、抗胰蛋白酶）成员3（SERPINA3）、白细胞介素1受体样1（IL1RL1）和血红蛋白β（HBB）。同样有趣的是α-突触核蛋白（SNCA）的可变剪接，以及存在一个与SNCA的3'外显子重叠的反义转录本。此外，我们证明了额叶皮质中广泛存在的反义转录，而这在很大程度上不受MSA特异性神经退行性过程的影响。MSA会导致人脑lincRNA以及与铁代谢和免疫反应调节相关的蛋白质编码基因的大量破坏。大多数MSA特异性的lincRNA是新发现的。因此，我们的研究揭示了MSA转录病理学中另一个复杂层面。
