Günaydın Caner, Çelik Z Betül, Bilge S Sırrı
Department of Pharmacology, School of Medicine, Samsun University, Samsun, Turkey.
Department of Histology and Embryology, School of Medicine, Ondokuz Mayıs University, Samsun, Turkey.
Immunopharmacol Immunotoxicol. 2022 Jun;44(3):447-455. doi: 10.1080/08923973.2022.2054427. Epub 2022 Mar 28.
Parkinson's disease (PD) is a chronic neurodegenerative disorder related with several genetic and epigenetic factors. In the context of epigenetic factors, histone acetylation is one of the most associated mechanisms with Parkinson's disease progression. This study investigates the effects of the increased histone acetylation on antigen presentation in microglial cells which were induced by pre-formed fibrils of α-synuclein (pFF α-synuclein).
Parkinson's disease model was created with pFF α-synuclein administration to the BV-2 microglial cells. BV-2 cells were co-treated with CUDC-907 and TMP-195 to increase histone acetylation in the presence of α-synuclein. Antigen representation was evaluated by determining expression levels of major histocompatibility complex-II (MHC-II) and class-II major histocompatibility complex (CIITA).
Our results showed that pFF α-synuclein significantly increased MHC-II expression, and that effect was most severe at 6 h of administration of α-synuclein. Increasing histone acetylation CUDC-907 and TMP-195 enhanced MHC-II levels expression, which was more severe in CUDC-907. Additionally, CIITA expression levels were significantly increased with pFF α-synuclein administration and intensified with the co-treatment of CUDC-907 and TMP-195. Furthermore, pFF α-synuclein caused a time-dependent increase in the IFN-gamma (IFN-ɣ) and interleukin-16(IL-16) levels, and that increase was potentiated with CUDC-907 and TMP-195.
Changes in MHC-II and CIITA expression indicate that histone acetylation increases the antigen presentation properties of microglial cells after pFF α-synuclein or histone deacetylase inhibitor (HDACi) administration. Our results show that microglial antigen presentation might have an essential role in the pathology of Parkinson's disease, and α-synuclein likely to play a primary role in this mechanism.
帕金森病（PD）是一种与多种遗传和表观遗传因素相关的慢性神经退行性疾病。在表观遗传因素的背景下，组蛋白乙酰化是与帕金森病进展最相关的机制之一。本研究调查了组蛋白乙酰化增加对由α-突触核蛋白预形成纤维（pFFα-突触核蛋白）诱导的小胶质细胞中抗原呈递的影响。
通过向BV-2小胶质细胞施用pFFα-突触核蛋白建立帕金森病模型。在存在α-突触核蛋白的情况下，BV-2细胞与CUDC-907和TMP-195共同处理以增加组蛋白乙酰化。通过测定主要组织相容性复合体-II（MHC-II）和II类主要组织相容性复合体（CIITA）的表达水平来评估抗原呈递。
我们的结果表明，pFFα-突触核蛋白显著增加MHC-II表达，并且在施用α-突触核蛋白6小时时该效应最为严重。增加组蛋白乙酰化的CUDC-907和TMP-195增强了MHC-II水平表达，在CUDC-907中更为严重。此外，施用pFFα-突触核蛋白后CIITA表达水平显著增加，并通过CUDC-907和TMP-195的共同处理而增强。此外，pFFα-突触核蛋白导致干扰素-γ（IFN-ɣ）和白细胞介素-16（IL-16）水平随时间依赖性增加，并且该增加在CUDC-907和TMP-195作用下增强。
MHC-II和CIITA表达的变化表明，在施用pFFα-突触核蛋白或组蛋白去乙酰化酶抑制剂（HDACi）后，组蛋白乙酰化增加了小胶质细胞的抗原呈递特性。我们的结果表明，小胶质细胞抗原呈递可能在帕金森病的病理过程中起重要作用，并且α-突触核蛋白可能在该机制中起主要作用。
