Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression.
Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression.
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DOI：
10.1186/s12974-021-02302-z
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发表时间：
2021-11-08
影响因子：
9.3
通讯作者：
Schwartz NB
中科院分区：
文献类型：
--
作者：
Domowicz MS;Chan WC;Claudio-Vázquez P;Gonzalez T;Schwartz NB
神经元蜡样脂褐素病(NCLS或Batten病)是一组与13个基因突变相关的遗传性、早发性、致死性神经退行性疾病。所有形式的疾病都以溶酶体积累荧光存储物质以及严重的神经变性为特征，但各种基因的功能与单一生物学过程的关系并不明显。在这项研究中，我们使用了一个典型的晚期婴儿NCL(CLINCL)小鼠模型，在该模型中，三肽基肽酶1(TPP1)基因被基因靶向干扰，导致可检测到的TPP1活性丧失，并导致进行性神经表型，包括共济失调、增加的运动障碍和早期死亡。为了确定可能有助于神经退化过程进展的基因和途径，我们通过全球RNA测序分析了对照组和TPP1基因缺陷小鼠在1、2、3和4个月龄时的前脑/中脑和小脑转录差异。进行性神经退行性炎症反应涉及小胶质细胞、星形胶质细胞和内皮细胞，并伴有白细胞外渗信号的激活，一氧化氮的产生和活性氧的上调。一些星形细胞(即GFAP、C4b、osmr、Serpina3n)和小胶质细胞(即CTSS、Itgb2、Itgax、Lyz2)基因被认为是评估疾病进展的强有力的标志，因为它们在体内的表达水平随着时间的推移而增加。此外，在2个月后观察到脉络丛基因在侧脑室和第四脑室的表达增加，突出了脉络丛和脑脊液在疾病病理中的早期作用。基于这些基因表达的变化，我们得出结论，在大部分情况下，神经炎症在Tpp1−/−脑中在2个月后开始，小脑中小胶质细胞和星形胶质细胞的激活比脑中其他部位发生得更快；证实了该区域炎症的严重性增加。这些发现有助于更好地了解cLINCL的病理发生和发展，这可能有助于开发未来治疗该疾病的方法。网上版载有补充材料，可在10.1186/s12974-021-02302-z查阅。
Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of fluorescent storage material, as well as profound neurodegeneration, but the relationship of the various genes’ function to a single biological process is not obvious. In this study, we used a well-characterized mouse model of classical late infantile NCL (cLINCL) in which the tripeptidyl peptidase 1 (Tpp1) gene is disrupted by gene targeting, resulting in loss of detectable TPP1 activity and leading to progressive neurological phenotypes including ataxia, increased motor deficiency, and early death. In order to identify genes and pathways that may contribute to progression of the neurodegenerative process, we analyzed forebrain/midbrain and cerebellar transcriptional differences at 1, 2, 3 and 4 months of age in control and TPP1-deficient mice by global RNA-sequencing. Progressive neurodegenerative inflammatory responses involving microglia, astrocytes and endothelial cells were observed, accompanied by activation of leukocyte extravasation signals and upregulation of nitric oxide production and reactive oxygen species. Several astrocytic (i.e., Gfap, C4b, Osmr, Serpina3n) and microglial (i.e., Ctss, Itgb2, Itgax, Lyz2) genes were identified as strong markers for assessing disease progression as they showed increased levels of expression in vivo over time. Furthermore, transient increased expression of choroid plexus genes was observed at 2 months in the lateral and fourth ventricle, highlighting an early role for the choroid plexus and cerebrospinal fluid in the disease pathology. Based on these gene expression changes, we concluded that neuroinflammation starts, for the most part, after 2 months in the Tpp1−/− brain and that activation of microglia and astrocytes occur more rapidly in cerebellum than in the rest of the brain; confirming increased severity of inflammation in this region. These findings have led to a better understanding of cLINCL pathological onset and progression, which may aid in development of future therapeutic treatments for this disease. The online version contains supplementary material available at 10.1186/s12974-021-02302-z.
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影响因子：
4.8
作者：
Campos-Melo D;Galleguillos D;Sánchez N;Gysling K;Andrés ME
通讯作者：
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DOI：
10.1016/j.bbadis.2006.08.002
发表时间：
2006-10-01
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作者：
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Kordower, JH
DOI：
10.1158/1078-0432.ccr-17-3673
发表时间：
2018-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bhanvadia RR;VanOpstall C;Brechka H;Barashi NS;Gillard M;McAuley EM;Vasquez JM;Paner G;Chan WC;Andrade J;De Marzo AM;Han M;Szmulewitz RZ;Vander Griend DJ
通讯作者：
Vander Griend DJ