Isik Finula I, Katzeff Jared S, Fu YuHong, Kim Woojin Scott
Brain and Mind Centre & School of Medical Sciences, The University of Sydney, Sydney NSW, Australia.
J Parkinsons Dis. 2023;13(8):1303-1311. doi: 10.3233/JPD-230298.
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. A major pathological feature of MSA is the presence of α-synuclein aggregates in oligodendrocytes, the myelinating cells of the central nervous system. A genome-wide association study revealed that the CDH4 gene is associated with MSA. However, virtually nothing is known about the role of CDH4 in the context of MSA.
Our aim was to compare the expression of CDH4 between MSA and control brains, and to investigate its relationship with α-synuclein in oligodendrocytes.
RNA and protein were prepared from putamen, motor cortex white matter, cerebellum, and superior occipital cortex tissues collected from MSA (N = 11) and control (N = 13) brains. The expression of CDH4 was measured at mRNA and protein levels by qPCR and western blotting. Oligodendrocyte cells were cultured on plates and transfected with CDH4 cDNA and its impact on α-synuclein was analyzed.
Firstly, we found that CDH4 in MSA brain was significantly elevated in the disease-affected motor cortex white matter in MSA (N = 11) compared to controls (N = 13) and unaltered in the disease-unaffected superior occipital cortex. Secondly, we determined that increases in CDH4 expression caused changes in the cellular levels of α-synuclein in oligodendrocytes.
When put together, these results provide evidence that support the GWAS association of CDH4 with MSA.
多系统萎缩（MSA）是一种快速进展的神经退行性疾病，临床特征为帕金森综合征、小脑共济失调和自主神经功能障碍。MSA的一个主要病理特征是在少突胶质细胞（中枢神经系统的髓鞘形成细胞）中存在α-突触核蛋白聚集体。一项全基因组关联研究表明，CDH4基因与MSA有关。然而，关于CDH4在MSA背景下的作用几乎一无所知。
我们的目的是比较MSA患者和对照者大脑中CDH4的表达，并研究其与少突胶质细胞中α-突触核蛋白的关系。
从MSA患者（N = 11）和对照者（N = 13）的大脑中收集壳核、运动皮质白质、小脑和枕叶上部皮质组织，制备RNA和蛋白质。通过qPCR和蛋白质印迹法在mRNA和蛋白质水平上测量CDH4的表达。将少突胶质细胞培养在培养板上，用CDH4 cDNA转染，并分析其对α-突触核蛋白的影响。
首先，我们发现与对照者（N = 13）相比，MSA患者（N = 11）中受疾病影响的运动皮质白质中CDH4显著升高，而在未受疾病影响的枕叶上部皮质中未发生变化。其次，我们确定CDH4表达的增加导致少突胶质细胞中α-突触核蛋白细胞水平的变化。
综合来看，这些结果提供了支持CDH4与MSA的全基因组关联研究的证据。
