Du Tingfu, Li Guoxiang, Zong Qinglan, Luo Haiyu, Pan Yue, Ma Kaili
Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, 650118, China.
Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Diseases, Kunming, 650118, China.
Immun Ageing. 2024 Jul 12;21(1):47. doi: 10.1186/s12979-024-00429-0.
The progression of Parkinson's disease (PD) is related to ageing. The accumulation of nuclear alpha-synuclein (α-syn) may accelerate the occurrence of neurodegenerative diseases, but its role in PD remains poorly understood.
In the present study, α-syn expression was specifically targeted to the nucleus by constructing an adeno-associated virus (AAV) vector in which a nuclear localization sequence (NLS) was added to the α-syn coding sequence. Virus-mediated gene transfer, behavioural tests, RNA-Seq, immunohistochemistry, western blotting, and quantitative real-time PCR were then performed.
In vivo experiments using a mouse model showed that nuclear α-syn increased the severity of the PD-like phenotype, including the loss of dopaminergic neurons concomitant with motor impairment and the formation of α-syn inclusions. These nuclear inclusions contained α-syn species of high molecular weights and induced strong transcriptional dysregulation, especially induced high expression of p21 and senescence-associated secretory phenotype (SASP)-related genes. In addition, the transcriptional alterations induced by nuclear α-syn were associated with gliosis, inflammation, oxidative and DNA damage, and lysosomal dysfunction, and they eventually accelerated neuronal loss and neurodegeneration.
Our results suggest that nuclear α-syn plays a crucial role in PD pathogenesis.
帕金森病（PD）的进展与衰老相关。核内α-突触核蛋白（α-syn）的积累可能会加速神经退行性疾病的发生，但其在PD中的作用仍知之甚少。
在本研究中，通过构建腺相关病毒（AAV）载体，将核定位序列（NLS）添加到α-syn编码序列中，使α-syn特异性定位于细胞核。然后进行病毒介导的基因转移、行为测试、RNA测序、免疫组织化学、蛋白质免疫印迹和定量实时PCR。
使用小鼠模型进行的体内实验表明，核内α-syn增加了PD样表型的严重程度，包括多巴胺能神经元的丧失以及运动功能障碍，同时伴有α-syn包涵体的形成。这些核内包涵体含有高分子量的α-syn物种，并诱导强烈的转录失调，特别是诱导p21和衰老相关分泌表型（SASP）相关基因的高表达。此外，核内α-syn诱导的转录改变与胶质增生、炎症、氧化和DNA损伤以及溶酶体功能障碍有关，最终加速了神经元丢失和神经退行性变。
我们的结果表明，核内α-syn在PD发病机制中起关键作用。
