Moore Justin, Wu Timothy, Dhindsa Justin, El Fadel Omar, Le Anh, Perez Alma, Amoh Bismark, Tarkunde Akash, Zhu Katy F, Avalos Matthew, Dammer Eric B, Duong Duc M, Seyfried Nicholas T, Shulman Joshua M, Al-Ramahi Ismael, Botas Juan
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Quantitative and Computational Bioscience Graduate Program, Baylor College of Medicine, Houston, TX, 77030, USA.
NPJ Parkinsons Dis. 2025 Mar 11;11(1):46. doi: 10.1038/s41531-025-00899-z.
Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated αSyn accelerates changes associated with normal aging. Unexpectedly, single-cell analysis at a mid-disease stage revealed that neurons upregulate protein synthesis and nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches in animal models can thus help elucidate the molecular cascades underlying neurodegeneration vs. aging and co-pathologies.
帕金森病（PD）在症状出现前数十年就已开始，通常在生命的后几十年，此时与年龄相关的变化正在发生。为了在疾病进程早期识别分子变化，并将PD病理与衰老区分开来，我们构建了在神经元中表达α-突触核蛋白（αSyn）的果蝇，并在其整个生命周期的六个时间点对大脑进行了纵向整体转录组学和蛋白质组学研究，并将数据与健康对照果蝇以及人类尸检脑数据集进行了比较。我们发现，在最早的时间点，αSyn果蝇的翻译和能量代谢途径被下调；与老年对照果蝇的比较表明，αSyn水平升高会加速与正常衰老相关的变化。出乎意料的是，在疾病中期阶段的单细胞分析显示，神经元上调蛋白质合成和无义介导的衰变，而神经胶质细胞则驱动它们整体下调。因此，动物模型中的纵向多组学方法有助于阐明神经退行性变与衰老及合并病理背后的分子级联反应。
