Failure of diet-induced transcriptional adaptations in A30P alpha-synuclein transgenic mice

Nutritional influences have been discussed as potential modulators of Parkinson’s disease (PD) pathology. In animal models, a high fat diet (HFD) with greater intake of lipid-derived calories leads to accelerated disease onset and progression. The underlying molecular mechanisms of HFD-induced aggravated pathology, however, remain largely unclear. In this study, we aimed to further illuminate the effects of a fat-enriched diet in PD by examining the brainstem and hippocampal transcriptome of alpha synuclein transgenic mice exposed to a life-long HFD. Investigating individual transcript isoforms, differential gene expression, and co-expression clusters, we observed that transcriptional differences between wildtype and transgenic animals intensified in both regions under HFD. Both brainstem and hippocampus displayed strikingly similar transcriptomic perturbation patterns. Interestingly, expression differences resulted mainly from responses in wildtype animals to HFD, while these genes remained largely unchanged or were even slightly oppositely regulated by diet in transgenic animals. Genes and co-expressed gene groups exhibiting this dysregulation were linked to metabolic and mitochondrial pathways. Our findings propose failure of metabolic adaptions as potential explanation for accelerated disease unfolding under exposure to HFD. From the identified clusters of co-expressed genes, several candidates lend themselves to further functional investigations. Four experimental groups in brainstem and hippocampus each: [Wildtype, Transgenic] x [standard diet, high fat diet]

营养因素已被视为帕金森病（Parkinson’s Disease, PD）病理进程的潜在调节因子。在动物模型中，伴随更高脂源性热量摄入的高脂饮食（High Fat Diet, HFD）可加速疾病的发作与进展。然而，高脂饮食诱导的病理加重效应背后的分子机制，在很大程度上仍未明确。
本研究旨在通过分析终身暴露于高脂饮食的α-突触核蛋白（α-synuclein）转基因小鼠的脑干与海马转录组，进一步阐明高脂饮食在帕金森病中的作用。通过对单个转录本异构体、差异基因表达及共表达簇展开分析，我们观察到：在高脂饮食干预下，野生型与转基因动物间的转录组差异在两个脑区均显著加剧。脑干与海马均呈现出高度相似的转录组扰动模式。
值得注意的是，表达差异主要源于野生型动物对高脂饮食的应答；而在转基因动物中，这类基因的表达水平基本未发生改变，甚至受到饮食的调控方向与野生型恰好相反。出现此类表达失调的基因及共表达基因簇，均与代谢通路及线粒体通路密切相关。
本研究结果表明，代谢适应能力受损可能是高脂饮食暴露下疾病进程加速的潜在机制。从已鉴定的共表达基因簇中，筛选出多个可用于后续功能研究的候选靶点。实验中脑干与海马各设置四组对照，分组方式为[野生型，转基因型] × [标准饮食，高脂饮食]