Regoni Maria, Zanetti Letizia, Sevegnani Martina, Domenicale Chiara, Magnabosco Stefano, Patel Jyoti C, Fernandes Megan K, Feeley Ryan M, Monzani Elena, Mini Cecilia, Comai Stefano, Cherchi Laura, De Gregorio Danilo, Soliman Isabella, Ruto Fabio, Croci Laura, Consalez Giacomo, Rodighiero Simona, Ciammola Andrea, Valtorta Flavia, Morari Michele, Piccoli Giovanni, Rice Margaret E, Sassone Jenny
Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Vita-Salute San Raffaele University, 20132 Milan, Italy.
Brain. 2024 Dec 3;147(12):4017-4025. doi: 10.1093/brain/awae276.
Mutations in the PRKN gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson's disease mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. To this end, we created a knock-in mouse carrying the homozygous PrknR275W mutation, which is the missense mutation with the highest allelic frequency in PRKN patients. We evaluated the anatomical and functional integrity of the nigrostriatal dopamine (DA) pathway, as well as motor behaviour in PrknR275W mice of both sexes. We report here that PrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that the PrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new Parkinson's disease model in which to study causative mechanisms of the disease and test therapeutic strategies.
编码帕金蛋白的PRKN基因突变会导致常染色体隐性遗传性青少年帕金森病（ARJP）。利用这种突变创建一个早发性帕金森病小鼠模型，将为阐明神经退行性变过程中涉及的机制提供独特机会，并为神经保护策略的开发奠定基础。为此，我们创建了一只携带纯合PrknR275W突变的敲入小鼠，该突变是PRKN患者中等位基因频率最高的错义突变。我们评估了黑质纹状体多巴胺（DA）通路的解剖和功能完整性，以及两性PrknR275W小鼠的运动行为。我们在此报告，PrknR275W小鼠表现出早期DA神经元功能障碍、黑质中DA神经元随年龄增长而丢失、纹状体中DA含量降低和刺激诱发的DA释放减少，以及进行性运动障碍。这些数据共同表明，PrknR275W小鼠概括了ARJP的关键特征。因此，这些研究通过引入一个有前景的新帕金森病模型来研究该疾病的致病机制并测试治疗策略，满足了该领域的一项关键需求。
