Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Acta Neuropathol. 2010 Jan;119(1):111-22. doi: 10.1007/s00401-009-0576-2. Epub 2009 Aug 2.
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.
额颞叶变性伴 TDP-43 包涵体（FTLD-TDP）的特征是行为、执行功能和语言逐渐下降。颗粒蛋白前体（GRN）基因突变是 FTLD-TDP 的致病因素，GRN 转录物单倍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；我们测量了大脑中的颗粒蛋白前体表达。我们从四个脑区（额叶皮质、颞叶皮质、枕叶皮质和小脑）的 FTLD-TDP 患者（有或无 GRN 突变）以及神经正常的个体中描述了 GRN 的 mRNA 和蛋白水平。此外，我们进行了免疫组织化学评估这些组中 TDP-43 病理学和小胶质细胞浸润的程度。在大多数脑区，携带 GRN 突变的患者的 mRNA 水平与正常对照和无 GRN 突变的 FTLD-TDP 患者相当。然而，在疾病严重受累的脑区（额叶皮质），携带突变的患者的 GRN 转录物水平增加。与正常个体相比，携带 GRN 突变的病例在小脑和枕叶皮质的颗粒蛋白前体蛋白含量显著减少，但在额叶和颞叶皮质则没有。在 GRN 突变病例中，GRN mRNA 来自正常等位基因，且观察到中等程度的小胶质细胞浸润。总之，GRN 突变携带者在脑中具有来自正常等位基因的高水平 mRNA 转录本，小胶质细胞的增殖可能会增加 FTLD-TDP 脑受累区域的颗粒蛋白前体水平，而这些发现是否构成与 GRN 突变相关的 FTLD-TDP 中 TDP-43 病理学的积累的基础仍有待确定。
