Brain and Mind Centre, Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, NSW 2050, Australia.
Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
Int J Mol Sci. 2022 May 6;23(9):5200. doi: 10.3390/ijms23095200.
Most neurodegenerative disorders take decades to develop, and their early detection is challenged by confounding non-pathological ageing processes. Therefore, the discovery of genes and molecular pathways in both peripheral and brain tissues that are highly predictive of disease evolution is necessary. To find genes that influence Alzheimer's disease (AD) and Parkinson's disease (PD) pathogenesis, human RNA-Seq transcriptomic data from Brodmann Area 9 (BA9) of the dorsolateral prefrontal cortex (DLPFC), whole blood (WB), and peripheral blood mononuclear cells (PBMC) were analysed using a combination of differential gene expression and a random forest-based machine learning algorithm. The results suggest that there is little overlap between PD and AD, and the AD brain signature is unique mainly compared to blood-based samples. Moreover, the AD-BA9 was characterised by changes in 'nervous system development' with Myocyte-specific enhancer factor 2C (), encoding a transcription factor that induces microglia activation, a prominent feature. The peripheral AD transcriptome was associated with alterations in 'viral process', and , which has been previously shown to link amyloid-beta and tau, was the prominent feature. However, in the absence of any overlap with the central transcriptome, it is unclear whether peripheral levels reflect AD severity or progression. In PD, central and peripheral signatures are characterised by anomalies in 'exocytosis' and specific genes related to the SNARE complex, including Vesicle-associated membrane protein 2 (), Syntaxin 1A (), and p21-activated kinase 1 (). This is consistent with our current understanding of the physiological role of alpha-synuclein and how alpha-synuclein oligomers compromise vesicle docking and neurotransmission. Overall, the results describe distinct disease-specific pathomechanisms, both within the brain and peripherally, for the two most common neurodegenerative disorders.
大多数神经退行性疾病需要数十年的时间才能发展，其早期检测受到混杂的非病理性衰老过程的挑战。因此，有必要在周围组织和脑组织中发现对疾病演变具有高度预测性的基因和分子途径。为了发现影响阿尔茨海默病 (AD) 和帕金森病 (PD) 发病机制的基因，使用差异基因表达和基于随机森林的机器学习算法对来自背外侧前额叶皮层 (DLPFC) 的 Brodmann 区 9 (BA9)、全血 (WB) 和外周血单核细胞 (PBMC) 的人类 RNA-Seq 转录组数据进行了分析。结果表明，PD 和 AD 之间几乎没有重叠，AD 大脑特征主要与基于血液的样本相比是独特的。此外，AD-BA9 的特征是“神经系统发育”的变化，编码一种诱导小胶质细胞激活的转录因子，这是一个突出的特征。外周 AD 转录组与“病毒过程”的改变有关，先前已显示与淀粉样蛋白-β和 tau 相关的，是突出的特征。然而，由于与中枢转录组没有任何重叠，尚不清楚外周水平是否反映 AD 的严重程度或进展。在 PD 中，中枢和外周特征以“胞吐作用”异常为特征，与 SNARE 复合物相关的特定基因，包括囊泡相关膜蛋白 2 ()、突触素 1A () 和 p21 激活激酶 1 ()，也是如此。这与我们目前对α-突触核蛋白生理作用的理解以及α-突触核蛋白寡聚物如何破坏囊泡停泊和神经传递一致。总体而言，这些结果描述了两种最常见的神经退行性疾病在大脑内和外周的特定疾病特异性病理机制。
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