Yan Minghao, Wu Huifang, Wu Tong, Wang Yuhan, Su Chengxiang, Li Dongmei, Han Xiaodong
State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.
Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China.
Mol Neurobiol. 2025 May;62(5):6195-6211. doi: 10.1007/s12035-024-04683-7. Epub 2024 Dec 30.
Microcystin-LR (MC-LR) is a natural neurotoxin with strong toxicity, and studies have demonstrated that chronic MC-LR exposure generated Parkinson-like dyskinesia in mice. Parkinson's disease (PD) is a neurologic degenerative disease mostly occurring in elderly people, and the progressive loss of dopaminergic neurons and the formation of Lewy bodies are the hallmark pathological features. The main component of Lewy bodies is α-synuclein (α-syn) encoded by the SNCA gene, and the copy number mutation of SNCA gene can promote the overexpression of α-syn. A mouse model of MC-LR exposure for 15 months was established to confirm the deposition of Lewy bodies. SH-SY5Y cells exposed to MC-LR were constructed as an in vitro model of PD, and the transcription factor that regulated the SNCA gene (the encoding gene of α-syn) was identified through the database. MC-LR enhanced the transcription level of SNCA gene and upregulated α-syn protein expression by promoting MAPK4 into the nucleus and binding to GATA2 295-480 fragment. In addition, MC-LR inhibited PP2A activity and activated GRKs kinase to promote α-syn phosphorylation at Ser129. These results suggest that MC-LR is involved in α-syn aggregate formation and PD pathogenesis by enhancing SNCA transcriptional activity to promote α-syn elevation via the MAPK4/GATA2 pathway and inducing α-syn phosphorylation via the PP2A/GRKs pathway.
微囊藻毒素-LR（MC-LR）是一种具有强毒性的天然神经毒素，研究表明，长期暴露于MC-LR会使小鼠产生帕金森样运动障碍。帕金森病（PD）是一种主要发生在老年人中的神经退行性疾病，多巴胺能神经元的进行性丧失和路易小体的形成是其标志性病理特征。路易小体的主要成分是由SNCA基因编码的α-突触核蛋白（α-syn），SNCA基因的拷贝数突变可促进α-syn的过表达。建立了暴露于MC-LR 15个月的小鼠模型以证实路易小体的沉积。构建暴露于MC-LR的SH-SY5Y细胞作为PD的体外模型，并通过数据库鉴定调节SNCA基因（α-syn的编码基因）的转录因子。MC-LR通过促进MAPK4进入细胞核并与GATA2 295-480片段结合，增强了SNCA基因的转录水平并上调了α-syn蛋白表达。此外，MC-LR抑制PP2A活性并激活GRKs激酶以促进α-syn在Ser129处的磷酸化。这些结果表明，MC-LR通过增强SNCA转录活性，经由MAPK4/GATA2途径促进α-syn升高，并通过PP2A/GRKs途径诱导α-syn磷酸化，从而参与α-syn聚集体的形成和PD发病机制。
