Patients with Parkinson’s disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in . Here, we introduce mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery.

中文翻译：

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秀丽隐杆线虫 RAC1/ced-10 突变体作为研究帕金森病早期阶段的新动物模型

帕金森病 (PD) 患者在运动体征出现之前和明确诊断之前就表现出非运动症状。运动和非运动症状与中枢神经系统内外蛋白质 α-突触核蛋白 (Asyn) 的逐渐沉积相关，其积累与神经退行性病变平行。的基因组不编码 Asyn 的同源物，因此使该线虫成为在没有内源 Asyn 聚集干扰的情况下研究 PD 相关机制的宝贵系统。 CED-10 是人类 RAC1 的线虫同源物，RAC1 是一种小型 GTP 酶，需要维持多巴胺能神经元的功能和存活，以抵抗人类 Asyn 诱导的毒性。在这里，我们引入突变体作为预测工具来研究神经变性发生之前的早期帕金森病症状。对这些动物的深入表型分析表明，在发育早期，它们表现出排便周期改变、GABA能异常和氧化指数增加。此外，它们表现出脂质代谢的改变，这可以通过脂滴的积累来证明。脂质组学指纹分析表明，突变线虫中磷脂酰胆碱和鞘磷脂升高，但磷脂酰乙醇胺或磷脂酰丝氨酸未升高。这些集体特征反映了非运动功能障碍、GABA能神经传递缺陷、应激反应机制的上调以及与早发性PD相关的代谢变化。因此，我们提出了一种易于操作的临床前动物模型，以加深我们对早期 PD 的理解，并加速治疗靶点发现的转化路径。