SNCA overexpression disturbs hippocampal gene expression trajectories in midlife
SNCA overexpression disturbs hippocampal gene expression trajectories in midlife
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DOI：
10.18632/aging.101691
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发表时间：
2018-12-01
期刊：
影响因子：
5.2
通讯作者：
Schulze-Hentrich, Julia M.
中科院分区：
文献类型：
--
作者：
Hentrich, Thomas;Wassouf, Zinah;Schulze-Hentrich, Julia M.
帕金森病和路易体痴呆等突触核蛋白病源于遗传倾向、年龄和环境因素之间复杂且仍然很大程度上神秘的相互作用。虽然运动功能逐渐衰退是晚年症状的标志，但这种疾病的最初迹象往往在中年几十年前就已经出现。为了更好地了解遗传、时间和环境方面的早期疾病阶段，我们研究了在不同环境下过度表达人类 SNCA（突触核蛋白病的关键基因）的小鼠模型在中年期间获得的海马转录组数据。为了将差异表达基因与人类联系起来，我们整合了衰老和帕金森病的表达特征。我们发现了两种独特的年龄依赖性紊乱模式：首先，细胞过程似乎激活得太早，反映了年龄的晚期阶段；其次，系统的典型纵向适应在中年时期不再发生。尽管 SNCA 持续过载，但环境浓缩阻止了这两种干扰模式。总之，我们的结果提醒人们这样一种观点，即 SNCA 相关病理学早期阶段特征的表达变化仅反映了加速衰老。相反，我们提供的证据表明，中年时期未能进行健康的适应是紊乱的第二个根源。这种双峰干扰原理可以为治疗工作提供信息，以区分针对疾病的预防性尝试和恢复性尝试。
Synucleinopathies like Parkinson's disease and dementia with Lewy bodies originate from a complex and still largely enigmatic interplay of genetic predisposition, age, and environmental factors. While progressively declining motor functions hallmark late-life symptoms, first signs of the disease often surface already decades earlier during midlife. To better understand early disease stages with respect to the genetic, temporal, and environmental dimension, we interrogated hippocampal transcriptome data obtained during midlife for a mouse model overexpressing human SNCA, a pivotal gene in synucleinopathies, under different environments. To relate differentially expressed genes to human, we integrated expression signatures for aging and Parkinson's disease. We identified two distinctive modes of age-dependent disturbances: First, cellular processes seemingly activated too early that reflected advanced stages of age and, second, typical longitudinal adaptations of the system that no longer occurred during midlife. Environmental enrichment prevented both disturbances modes despite persistent SNCA overload. Together, our results caution the view that expression changes characterising early stages of SNCA-related pathology reflect accelerated aging alone. Instead, we provide evidence that failure to undergo healthy adaptions during midlife represents a second origin of disturbances. This bimodal disturbance principle could inform therapeutic efforts to distinguish between preventive and restorative attempts to target the disease.