Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Veterans Affairs Medical Center, Lexington, Kentucky, USA.
Genes Brain Behav. 2024 Aug;23(4):e12911. doi: 10.1111/gbb.12911.
Neutral sphingomyelinase-2 (nSMase2), gene name sphingomyelin phosphodiesterase-3 (Smpd3), is a key regulatory enzyme responsible for generating the sphingolipid ceramide. The function of nSMase2 in the brain is still controversial. To better understand the functional roles of nSMase2 in the aging mouse brain, we applied RNA-seq analysis, which identified a total of 1462 differentially abundant mRNAs between +/fro and fro/fro, of which 891 were increased and 571 were decreased in nSMase2-deficient mouse brains. The most strongly enriched GO and KEGG annotation terms among transcripts increased in fro/fro mice included synaptogenesis, synapse development, synaptic signaling, axon development, and axonogenesis. Among decreased transcripts, enriched annotations included ribosome assembly and mitochondrial protein complex functions. KEGG analysis of decreased transcripts also revealed overrepresentation of annotations for Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington disease (HD). Ingenuity Pathway Analysis (IPA) tools predicted lower susceptibility to these neurodegenerative disorders, as well as predictions agreeing with stronger synaptic function, learning, and memory in fro/fro mice. The IPA tools identified signaling proteins, epigenetic regulators, and microRNAs as likely upstream regulators of the broader set of genes encoding the affected transcripts. It also revealed 16 gene networks, each linked to biological processes identified as overrepresented annotations among the affected transcripts by multiple analysis methods. Therefore, the analysis of these RNA-seq data indicates that nSMase2 impacts synaptic function and neural development, and may contribute to the onset and development of neurodegenerative diseases in middle-aged mice.
中性鞘磷脂酶-2（nSMase2），基因名称鞘磷脂磷酸二酯酶-3（Smpd3），是一种关键的调节酶，负责生成鞘脂神经酰胺。nSMase2 在大脑中的功能仍存在争议。为了更好地理解 nSMase2 在衰老小鼠大脑中的功能作用，我们应用 RNA-seq 分析，共鉴定出+/fro 和 fro/fro 之间 1462 个差异丰度的 mRNA，其中 891 个在 nSMase2 缺陷型小鼠大脑中增加，571 个减少。在 fro/fro 小鼠中增加的转录物中，最富集的 GO 和 KEGG 注释术语包括突触发生、突触发育、突触信号转导、轴突发育和轴突发生。在减少的转录物中，富集的注释包括核糖体组装和线粒体蛋白复合物功能。减少的转录物的 KEGG 分析也揭示了阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病（HD）注释的过度表达。京都基因与基因组百科全书（KEGG）分析还预测 fro/fro 小鼠对这些神经退行性疾病的易感性降低，以及与更强的突触功能、学习和记忆相一致的预测。IPA 工具预测 fro/fro 小鼠对这些神经退行性疾病的易感性降低，以及与更强的突触功能、学习和记忆相一致的预测。IPA 工具预测 fro/fro 小鼠对这些神经退行性疾病的易感性降低，以及与更强的突触功能、学习和记忆相一致的预测。IPA 工具确定了信号蛋白、表观遗传调节剂和 microRNAs 作为受影响转录物编码的更广泛基因的潜在上游调节剂。它还揭示了 16 个基因网络，每个网络都与生物过程相关，这些生物过程被多种分析方法确定为受影响转录物中过度表达的注释。因此，这些 RNA-seq 数据的分析表明，nSMase2 影响突触功能和神经发育，并可能导致中年小鼠神经退行性疾病的发生和发展。
