Breznik Livia, Daurer Magdalena, Rabl Roland, Loeffler Tina, Etxeberria-Rekalde Estibaliz, Neddens Joerg, Flunkert Stefanie, Prokesch Manuela
Scantox Neuro GmbH, Grambach, Austria.
Front Neurosci. 2024 Sep 20;18:1462041. doi: 10.3389/fnins.2024.1462041. eCollection 2024.
Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of α-synuclein (α-syn) aggregates. The A53T missense point mutation occurs in autosomal dominant familial PD and has been found to promote the aggregation of α-syn. To investigate the role of the A53T mutation in PD, researchers have developed various mouse models with this mutation.
We therefore conducted a comprehensive characterization of the tg(THY1-SNCA*A53T)M53Sud mouse model (hA53Ttg mice) for its motor and pathological features.
hA53Ttg mice were tested for motor impairments in a series of motor tests at 2, 4 or 6 months of age. Human α-syn and α-syn pSer129, as well as GFAP and Iba1 signal were labeled and quantified in the cortex, hippocampus, and brainstem. Neurofilament light chain (NF-L) levels were measured in the cerebrospinal fluid (CSF) and plasma. analyses were performed at the age of 2, 4, 6, and 10 months.
Behavioral tests revealed early muscle weakness and motor impairments that progressed with age. Immunohistochemical analyses demonstrated elevated levels of human α-syn and α-syn pSer129 in all evaluated brain regions. α-syn pSer129 labeling further revealed fiber-like structures in the cortex of older animals. Neuroinflammation was observed in an age-dependent manner. Biochemical evaluation revealed elevated NF-L levels in the plasma and CSF. Overall, our findings highlight the value of hA53Ttg mice in modeling PD-associated pathologies that closely resemble those observed in PD patients.
Our results thus suggest that hA53Ttg mice are a useful tool for studying the underlying mechanisms of PD.
帕金森病（PD）是一种使人衰弱的神经退行性疾病，其特征是多巴胺能神经元逐渐丧失以及α-突触核蛋白（α-syn）聚集体的积累。A53T错义点突变发生在常染色体显性遗传性家族性帕金森病中，并且已被发现可促进α-syn的聚集。为了研究A53T突变在帕金森病中的作用，研究人员已经开发出了多种带有此突变的小鼠模型。
因此，我们对tg(THY1-SNCA*A53T)M53Sud小鼠模型（hA53Ttg小鼠）的运动和病理特征进行了全面表征。
在2、4或6月龄时，通过一系列运动测试对hA53Ttg小鼠的运动损伤进行检测。对皮质、海马体和脑干中的人α-syn和α-syn pSer129以及胶质纤维酸性蛋白（GFAP）和离子钙结合衔接分子1（Iba1）信号进行标记和定量。测量脑脊液（CSF）和血浆中的神经丝轻链（NF-L）水平。在2、4、6和10月龄时进行分析。
行为测试显示早期肌肉无力和运动损伤，并随年龄增长而加重。免疫组织化学分析表明，在所有评估的脑区中，人α-syn和α-syn pSer129的水平均升高。α-syn pSer129标记进一步揭示了老年动物皮质中的纤维样结构。观察到神经炎症呈年龄依赖性。生化评估显示血浆和脑脊液中的NF-L水平升高。总体而言，我们的研究结果突出了hA53Ttg小鼠在模拟与帕金森病患者中观察到的病理情况极为相似的帕金森病相关病理方面的价值。
因此，我们的结果表明hA53Ttg小鼠是研究帕金森病潜在机制的有用工具。
