将草履虫 RAC1/ced-10 突变体作为研究帕金森病早期阶段的新动物模型。

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2024-01-20 DOI:10.1016/j.pneurobio.2024.102572
A. Muñoz-Juan , N. Benseny-Cases , S. Guha , I. Barba , K.A. Caldwell , G.A Caldwell , L. Agulló , V.J. Yuste , A. Laromaine , E. Dalfó
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引用次数: 0

摘要

帕金森病(PD)患者在出现运动症状之前和明确诊断之前会出现非运动症状。运动症状和非运动症状与α-突触核蛋白(Asyn)在中枢神经系统内外的进行性沉积有关,其积累与神经变性平行。秀丽隐杆线虫的基因组不编码 Asyn 的同源物,因此在没有内源性 Asyn 聚集干扰的情况下,这种线虫是研究与帕金森病相关机制的宝贵系统。CED-10 是人类 RAC1 的线虫同源物,RAC1 是维持多巴胺能神经元功能和存活所需的一种小 GTPase,可对抗 elegans 中人类 Asyn 诱导的毒性。在这里,我们将 elegans RAC1/ced-10 突变体作为一种预测工具,用于研究神经变性发生之前的早期帕金森病症状。对这些动物的深度表型分析表明,它们在发育早期就表现出排便周期改变、GABA能异常和氧化指数增加。此外,它们的脂质代谢也发生了改变,表现为脂滴的积累。脂质体指纹图谱显示,RAC1/ced-10突变体线虫的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没有升高。这些综合特征反映了与早发性脊髓灰质炎相关的非运动功能障碍、GABA能神经递质缺陷、应激反应机制上调和代谢变化。因此,我们提出了一种易于操作的临床前动物模型,以加深我们对早期帕金森病的理解,并加速治疗靶点发现的转化途径。
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Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson’s disease

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 Caenorhabditis elegans 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 C. elegans. Here, we introduce C. elegans RAC1/ced-10 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 RAC1/ced-10 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.

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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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