mdx营养不良脑中分子和功能异常的时空多样性。

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Joanna Pomeroy, Malgorzata Borczyk, Maria Kawalec, Jacek Hajto, Emma Carlson, Samuel Svärd, Suraj Verma, Eric Bareke, Anna Boratyńska-Jasińska, Dorota Dymkowska, Alvaro Mellado-Ibáñez, David Laight, Krzysztof Zabłocki, Annalisa Occhipinti, Loydie Majewska, Claudio Angione, Jacek Majewski, Gennady G Yegutkin, Michal Korostynski, Barbara Zabłocka, Dariusz C Górecki
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引用次数: 0

摘要

杜氏肌营养不良症(DMD)以进行性肌肉变性和神经精神异常为特征。全长肌营养不良蛋白的丧失是启动DMD的必要和充分条件。这些亚型在海马、大脑皮层(Dp427c)和小脑浦肯野细胞(Dp427p)中表达。然而,我们对缺乏它们的后果的理解仍然不足,这对制定有针对性的干预措施至关重要。我们将RNA测序与基因组尺度代谢模型(GSMM)、免疫检测和线粒体分析相结合,研究mdx小鼠DMD模型大脑中的营养不良改变。分别对大脑和小脑进行分析,以确定Dp427c和Dp427p的作用。在10天(10d)和10周(10w)时对这些区域进行调查,跟踪异常从发育到成年早期的演变。这些时间点还包括发病前和肌肉炎症期间,从而能够评估炎症介质穿过营养不良的血脑屏障所造成的潜在损伤。我们首次证明了转录组学和功能性营养不良的改变是大脑和小脑所特有的,并且在10d和10w之间变化很大。常见的异常包括mdx转录本中保留的内含子和剪接的外显子数量的改变,这与mRNA加工途径的改变相对应。大脑的异常在年轻的老鼠身上更为明显。最富集的通路包括与代谢、mRNA加工和神经元发育相关的通路。GSMM提示糖代谢失调,与GLUT1蛋白下调相对应。小脑营养不良的转录组,虽然显著改变,但显示出与大脑相反的轨迹,在10天内几乎没有发现变化。这些晚期缺陷是特异性的,并表明对出生后小脑功能成熟的影响。虽然在10周时没有检测到经典的神经炎症标志物或小胶质细胞激活,但特异性差异表明炎症会影响DMD大脑。重要的是,一些营养不良改变发生较晚,因此可能适合治疗干预,为减轻dmd相关的神经精神缺陷提供了潜在的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Spatiotemporal diversity in molecular and functional abnormalities in the mdx dystrophic brain.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration and neuropsychiatric abnormalities. Loss of full-length dystrophins is both necessary and sufficient to initiate DMD. These isoforms are expressed in the hippocampus, cerebral cortex (Dp427c), and cerebellar Purkinje cells (Dp427p). However, our understanding of the consequences of their absence, which is crucial for developing targeted interventions, remains inadequate. We combined RNA sequencing with genome-scale metabolic modelling (GSMM), immunodetection, and mitochondrial assays to investigate dystrophic alterations in the brains of the mdx mouse model of DMD. The cerebra and cerebella were analysed separately to discern the roles of Dp427c and Dp427p, respectively. Investigating these regions at 10 days (10d) and 10 weeks (10w) followed the evolution of abnormalities from development to early adulthood. These time points also encompass periods before onset and during muscle inflammation, enabling assessment of the potential damage caused by inflammatory mediators crossing the dystrophic blood-brain barrier. For the first time, we demonstrated that transcriptomic and functional dystrophic alterations are unique to the cerebra and cerebella and vary substantially between 10d and 10w. The common anomalies involved altered numbers of retained introns and spliced exons across mdx transcripts, corresponding with alterations in the mRNA processing pathways. Abnormalities in the cerebra were significantly more pronounced in younger mice. The top enriched pathways included those related to metabolism, mRNA processing, and neuronal development. GSMM indicated dysregulation of glucose metabolism, which corresponded with GLUT1 protein downregulation. The cerebellar dystrophic transcriptome, while significantly altered, showed an opposite trajectory to that of the cerebra, with few changes identified at 10 days. These late defects are specific and indicate an impact on the functional maturation of the cerebella that occurs postnatally. Although no classical neuroinflammation markers or microglial activation were detected at 10 weeks, specific differences indicate that inflammation impacts DMD brains. Importantly, some dystrophic alterations occur late and may therefore be amenable to therapeutic intervention, offering potential avenues for mitigating DMD-related neuropsychiatric defects.

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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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