Trautwig Adam N, Shantaraman Anantharaman, Chung Mingee, Dammer Eric B, Ping Lingyan, Duong Duc M, Petrucelli Leonard, Ward Michael E, Glass Jonathan D, Nelson Peter T, Levey Allan I, McEachin Zachary T, Seyfried Nicholas T
Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
bioRxiv. 2025 Jun 3:2025.05.30.656396. doi: 10.1101/2025.05.30.656396.
TDP-43 pathology is a defining feature of Limbic-Predominant Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) and is frequently comorbid with Alzheimer's disease neuropathologic change (ADNC). However, the molecular consequences of co-occurring LATE-NC and ADNC pathology (TDP-43, β-amyloid, and tau protein pathologies) remain unclear. Here, we conducted a comparative biochemical, molecular, and proteomic analysis of hippocampal tissue from 90 individuals spanning control, LATE-NC, ADNC, and ADNC+LATE-NC groups to assess the impact of cryptic exon (CE) inclusion, phosphorylated TDP-43 pathology (pTDP-43), and AD-related pathologies (β-amyloid, and tau) on the proteome. ADNC+LATE-NC cases exhibited the highest burden of CE inclusion as quantified by measuring the levels of known TDP-43 regulated CEs within eight transcripts: and . While CE levels correlated with pTDP-43 pathology, they were more strongly correlated with each other, suggesting that the molecular signature of CE inclusion may serve as a more sensitive measure of TDP-43 dysfunction than pTDP-43 pathology alone. Unbiased classification based on the relative abundance of these eight CEs stratified individual cases into low, intermediate, and high CE burden subtypes, largely independent of β-amyloid and tau pathology. Proteome-wide correlation analysis revealed a bias toward reduced protein levels from genes harboring TDP-43-regulated CEs in cases with high cumulative CE burden. Notably, proteins significantly decreased under high CE burden included canonical STMN2, ELAVL3, and KALRN, as well as kinesin proteins that are genetically associated with amyotrophic lateral sclerosis. Co-expression network analysis identified both shared and distinct biological processes across CE subtypes and pathways associated with pTDP-43, tau, β-amyloid pathologies, and CE accumulation in the hippocampus. Protein modules associated with TDP-43 loss of function were prioritized by integrating proteomic data from TDP-43-depleted human neurons with the hippocampal co-expression network. Specifically, we observed decreased endosomal vesicle, microtubule-binding, and synaptic modules, alongside an increase in RNA-binding modules. These results provide new insights into the proteomic impact of CE burden across the spectrum of LATE and AD pathological severity, highlighting the molecular consequences of TDP-43 dysfunction in neurodegenerative disease.
TDP-43病理学是边缘叶为主的年龄相关性TDP-43脑病神经病理改变（LATE-NC）的一个决定性特征，并且经常与阿尔茨海默病神经病理改变（ADNC）合并存在。然而，LATE-NC和ADNC病理学共同出现（TDP-43、β-淀粉样蛋白和tau蛋白病理学）的分子后果仍不清楚。在此，我们对90名个体的海马组织进行了比较性生物化学、分子和蛋白质组学分析，这些个体分属对照、LATE-NC、ADNC以及ADNC+LATE-NC组，以评估隐匿外显子（CE）包含、磷酸化TDP-43病理学（pTDP-43）以及AD相关病理学（β-淀粉样蛋白和tau）对蛋白质组的影响。通过测量八个转录本中已知的TDP-43调控的CE水平进行定量分析，结果显示ADNC+LATE-NC病例的CE包含负担最高。虽然CE水平与pTDP-43病理学相关，但它们之间的相关性更强，这表明CE包含的分子特征可能比单独的pTDP-43病理学更能敏感地衡量TDP-43功能障碍。基于这八个CE的相对丰度进行的无偏分类将个体病例分为低、中、高CE负担亚型，在很大程度上独立于β-淀粉样蛋白和tau病理学。全蛋白质组相关性分析显示，在累积CE负担高的病例中，含有TDP-43调控的CE的基因的蛋白质水平有降低的趋势。值得注意的是，在高CE负担下显著减少的蛋白质包括典型的STMN2、ELAVL3和KALRN，以及与肌萎缩侧索硬化症在遗传上相关的驱动蛋白。共表达网络分析确定了跨CE亚型以及与pTDP-43、tau、β-淀粉样蛋白病理学和海马体中CE积累相关的途径中共享和不同的生物学过程。通过将来自TDP-43缺失的人类神经元的蛋白质组学数据与海马体共表达网络相结合，对与TDP-43功能丧失相关的蛋白质模块进行了优先排序。具体而言，我们观察到内体小泡、微管结合和突触模块减少，同时RNA结合模块增加。这些结果为LATE和AD病理严重程度范围内CE负担的蛋白质组学影响提供了新的见解，突出了TDP-43功能障碍在神经退行性疾病中的分子后果。
