Pathological characteristics of axons and alterations of proteomic and lipidomic profiles in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.

IF 14.9 1区 医学 Q1 NEUROSCIENCES Molecular Neurodegeneration Pub Date : 2024-08-26 DOI:10.1186/s13024-024-00746-4
Panpan Wang, Yaping Shao, Murad Al-Nusaif, Jun Zhang, Huijia Yang, Yuting Yang, Kunhyok Kim, Song Li, Cong Liu, Huaibin Cai, Weidong Le
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Abstract

Background: Although WD repeat domain 45 (WDR45) mutations have been linked to β -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system.

Methods: To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration.

Results: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits.

Conclusions: In this study, we uncovered the molecular mechanisms underlying the contribution of WDR45 deficiency to axonal degeneration, which involves complex relationships between phospholipid metabolism, autophagy, and tubular ER. These findings greatly advance our understanding of the fundamental molecular mechanisms driving axonal degeneration and may provide a foundation for developing novel mechanistically based therapeutic interventions for BPAN and other neurodegenerative diseases.

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WDR45缺陷诱导的中脑多巴胺能神经变性中轴突的病理特征以及蛋白质组和脂质组特征的改变
背景:尽管WD重复结构域45(WDR45)突变与β-丙种球蛋白相关神经变性(BPAN)有关,但这种疾病背后的确切分子和细胞机制仍然难以捉摸。本研究旨在揭示 WDR45 缺陷对中脑多巴胺能(DAergic)系统内神经变性(特别是轴索变性)的影响。我们希望通过研究病理和分子改变,尤其是多巴胺能系统内的病理和分子改变,更好地了解疾病的过程:为了研究WDR45功能障碍对小鼠行为和DA能神经元的影响,我们建立了一个小鼠模型,在该模型中,WDR45在中脑DA能神经元中被有条件地敲除(WDR45cKO)。通过一项纵向研究,我们使用开阔地、旋转木马、Y-迷宫和三室社会接近测试评估了小鼠行为的改变。我们采用免疫荧光染色和透射电子显微镜相结合的方法来检测DA能神经元体节和轴突的病理变化。此外,我们还对年轻小鼠和衰老小鼠的纹状体进行了蛋白质组和脂质组分析,以确定可能参与衰老过程中纹状体病理变化的分子和过程。此外,我们还利用原代中脑神经元培养来探索导致轴突变性的分子机制:我们对WDR45cKO小鼠的研究发现,小鼠的运动功能受损、情绪不稳定、记忆力减退等一系列缺陷都与中脑DA能神经元的严重减少有关。在神经元缺失的同时,我们观察到背侧和腹侧纹状体的轴突大量增大。这些肿大的特征是广泛破碎的管状内质网(ER)堆积,这是轴突变性的标志。纹状体的蛋白质组分析表明,差异表达的蛋白质富集在代谢过程中。碳水化合物代谢和蛋白质分解代谢过程出现较早,而氨基酸、脂质和三羧酸代谢在衰老过程中有所增加。值得注意的是,我们观察到溶血磷脂酰胆碱酰基转移酶 1(Lpcat1)的表达量大幅增加,该酶调节磷脂代谢,特别是在有酰基-CoA 存在的情况下将溶血磷脂酰胆碱(LPC)转化为磷脂酰胆碱(PC)。脂质体组学结果一致表明,不同的脂质集中在 PC 和 LPC 上。在原代培养的WDR45缺陷DA能神经元中干扰Lpcat1的表达可有效改善轴突变性,证明Lpcat1及其调控的脂质代谢,尤其是PC和LPC代谢参与控制WDR45缺陷诱导的轴突变性:本研究揭示了WDR45缺陷导致轴突变性的分子机制,其中涉及磷脂代谢、自噬和管状ER之间的复杂关系。这些发现极大地促进了我们对驱动轴突变性的基本分子机制的理解,并可能为开发基于机理的新型治疗干预措施以治疗 BPAN 和其他神经退行性疾病奠定基础。
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来源期刊
Molecular Neurodegeneration
Molecular Neurodegeneration 医学-神经科学
CiteScore
23.00
自引率
4.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels. Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.
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