Department of Neurology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaecho, Itabashi, Tokyo 173-0015, Japan.
Brain Res. 2018 Oct 15;1697:59-66. doi: 10.1016/j.brainres.2018.06.017. Epub 2018 Jun 15.
Lewy body disease (LBD) is characterized by accumulation of aggregated α-synuclein in the central nervous system as eosinophilic cytoplasmic inclusions called Lewy bodies. According to their distribution pattern, it is classified into brainstem LBD, limbic LBD and diffuse neocortical LBD. It has been reported that α-synuclein affects various points in the MAPK cascade but its relationship with FGF receptors, which are the most upstream of the pathway, has not been previously investigated. We discovered that among the four FGFRs, FGFR3 showed neuronal upregulation in LBD brains histopathologically. Further examination using neuron-specific methylome analysis revealed that the gene body of FGFR3 was hypermethylated in LBD, suggesting its increased transcription. Altered methylation was not observed in the non-neuronal genome. Altered methylation status was associated with the severity of α-synuclein pathology.
路易体病（LBD）的特征是在中枢神经系统中聚集的 α-突触核蛋白积累为嗜酸性细胞质包涵体，称为路易体。根据其分布模式，它可分为脑干 LBD、边缘叶 LBD 和弥漫性新皮质 LBD。据报道，α-突触核蛋白影响 MAPK 级联中的各个点，但它与 FGF 受体的关系（该受体是该途径中最上游的）以前尚未被研究过。我们发现，在四个 FGFR 中，FGFR3 在 LBD 大脑的组织病理学上表现出神经元上调。进一步使用神经元特异性甲基组分析的检查表明，LBD 中 FGFR3 的基因体发生了过度甲基化，提示其转录增加。在非神经元基因组中未观察到改变的甲基化。改变的甲基化状态与 α-突触核蛋白病理学的严重程度相关。
