Brain progranulin expression in GRN-associated frontotemporal lobar degeneration.
Brain progranulin expression in GRN-associated frontotemporal lobar degeneration.
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在与GRN相关的额颞Lobar变性中，脑前素蛋白表达。
DOI：
10.1007/s00401-009-0576-2
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发表时间：
2010-01
影响因子：
12.7
通讯作者：
Lee VM
中科院分区：
文献类型：
--
作者：
Chen-Plotkin AS;Xiao J;Geser F;Martinez-Lage M;Grossman M;Unger T;Wood EM;Van Deerlin VM;Trojanowski JQ;Lee VM
伴有 TDP-43 包涵体的额颞叶变性 (FTLD-TDP) 的特点是行为、执行功能和语言进行性下降。颗粒体蛋白前体 (GRN) 基因突变是 FTLD-TDP 的致病因素，GRN 转录单倍体不足是拟议的疾病机制。然而，这一假设的证据主要来自于血液来源的细胞。我们测量了大脑中颗粒体蛋白前体的表达。我们对有或没有 GRN 突变的 FTLD-TDP 患者以及神经系统正常个体的四个脑区（额叶皮层、颞叶皮层、枕叶皮层和小脑）的颗粒体蛋白前体 mRNA 和蛋白质水平进行了表征。此外，我们进行了免疫组织化学来评估这些组中 TDP-43 病理学和小胶质细胞浸润的程度。在大多数大脑区域，GRN 突变患者的 mRNA 水平与正常对照和无 GRN 突变的 FTLD-TDP 相当。然而，在携带突变的患者中，受疾病严重影响的大脑区域（额叶皮层）的 GRN 转录水平升高。与正常个体相比，携带GRN突变的病例小脑和枕叶皮层中颗粒体蛋白前体的数量显着减少，但额叶和颞叶皮层中的颗粒体蛋白前体蛋白数量没有显着减少。在 GRN 突变病例中，GRN mRNA 源自正常等位基因，并观察到中度小胶质细胞浸润。总之，GRN 突变携带者大脑中正常等位基因的 mRNA 转录物水平增加，小胶质细胞的增殖可能增加 FTLD-TDP 大脑受影响区域的颗粒体蛋白前体水平，这些发现是否是与 GRN 突变相关的 FTLD-TDP 中 TDP-43 病理积累的基础仍有待确定。
Frontotemporal lobar degeneration with TDP- 43 inclusions (FTLD-TDP) is characterized by progressive decline in behavior, executive function, and language. Progranulin (GRN) gene mutations are pathogenic for FTLD-TDP, and GRN transcript haploinsufficiency is the proposed disease mechanism. However, the evidence for this hypothesis comes mainly from blood-derived cells; we measured progranulin expression in brain. We characterized mRNA and protein levels of progranulin from four brain regions (frontal cortex, temporal cortex, occipital cortex, and cerebellum) in FTLD-TDP patients with and without GRN mutations, as well as neurologically normal individuals. Moreover, we performed immunohistochemistry to evaluate the degree of TDP-43 pathology and microglial infiltration present in these groups. In most brain regions, patients with GRN mutations showed mRNA levels comparable to normal controls and to FTLD-TDP without GRN mutations. However, GRN transcript levels in a brain region severely affected by disease (frontal cortex) were increased in mutation-bearing patients. When compared with normal individuals, GRN mutation-bearing cases had a significant reduction in the amount of progranulin protein in the cerebellum and occipital cortex, but not in the frontal and temporal cortices. In GRN mutant cases, GRN mRNA originated from the normal allele, and moderate microglial infiltration was observed. In conclusion, GRN mutation carriers have increased levels of mRNA transcript from the normal allele in brain, and proliferation of microglia likely increases progranulin levels in affected regions of the FTLD-TDP brain, and whether or not these findings underlie the accumulation of TDP-43 pathology in FTLD-TDP linked to GRN mutations remains to be determined.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
82.9
作者：
He, ZH;Ong, CHP;Bateman, A
通讯作者：
Bateman, A
影响因子：
4.8
作者：
BHANDARI, V;GIAID, A;BATEMAN, A
通讯作者：
BATEMAN, A
影响因子：
3.5
作者：
Chen-Plotkin, Alice S.;Geser, Felix;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
影响因子：
--
作者：
Geser, Felix;Brandmeir, Nicholas J.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.