In humans, homozygous mutations in the TPP1 gene results in loss of tripeptidyl peptidase 1 (TPP1) enzymatic activity, leading to late infantile neuronal ceroid lipofuscinoses disease. Using a mouse model that targets the Tpp1 gene and recapitulates the pathology and clinical features of the human disease, we analyzed end-stage (4 months) transcriptional changes associated with lack of TPP1 activity. Using RNA sequencing technology, Tpp1 expression changes in the forebrain/midbrain and cerebellum of 4-month-old homozygotes were compared with strain-related controls. Transcriptional changes were found in 510 and 1,550 gene transcripts in forebrain/midbrain and cerebellum, respectively, from Tpp1-deficient brain tissues when compared with age-matched controls. Analysis of the differentially expressed genes using the Ingenuity™ pathway software, revealed increased neuroinflammation activity in microglia and astrocytes that could lead to neuronal dysfunction, particularly in the cerebellum. We also observed upregulation in the production of nitric oxide and reactive oxygen species; activation of leukocyte extravasation signals and complement pathways; and downregulation of major transcription factors involved in control of circadian rhythm. Several of these expression changes were confirmed by independent quantitative polymerase chain reaction and histological analysis by mRNA in situ hybridization, which allowed for an in-depth anatomical analysis of the pathology and provided independent confirmation of at least two of the major networks affected in this model. The identification of differentially expressed genes has revealed new lines of investigation for this complex disorder that may lead to novel therapeutic targets.

中文翻译：

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Tpp1神经元脂质脂褐素小鼠模型的全球脑转录组分析。

在人类中，TPP1基因的纯合突变导致三肽基肽酶1（TPP1）的酶活性丧失，从而导致晚期婴儿神经元类固醇脂褐藻病。使用靶向Tpp1基因并概述人类疾病的病理和临床特征的小鼠模型，我们分析了与TPP1活性缺乏相关的终末（4个月）转录变化。使用RNA测序技术，将4个月大纯合子的前脑/中脑和小脑中Tpp1表达的变化与菌株相关对照进行了比较。与年龄匹配的对照组相比，分别在Tpp1缺陷型脑组织的前脑/中脑和小脑的510和1,550个基因转录物中发现了转录变化。使用Ingenuity™途径软件分析差异表达的基因，提示小胶质细胞和星形胶质细胞的神经炎症活动增加，可能导致神经元功能异常，尤其是小脑。我们还观察到一氧化氮和活性氧的产生上调。激活白细胞外渗信号和补体途径；和下调与昼夜节律有关的主要转录因子。这些表达变化中的一些已通过独立的定量聚合酶链反应和mRNA原位杂交的组织学分析得到了证实，这使得可以对病理学进行深入的解剖学分析，并独立证实了该模型中受影响的至少两个主要网络。