Departments of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Acta Neuropathol Commun. 2013 Jul 11;1:36. doi: 10.1186/2051-5960-1-36.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease.
Since little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations.
Our data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP.
额颞叶变性（FTLD）是 65 岁以下人群第二常见的痴呆病因，其特征为额颞叶变性导致行为、人格或语言改变。FTLD-TDP 是 FTLD 最大的神经病理学亚型，其特征为 TAR DNA 结合蛋白 43（TDP-43）异常磷酸化和泛素化包涵体。颗粒体蛋白（GRN）基因突变是 FTLD-TDP 最常见的孟德尔遗传病因之一，GRN 是一种神经保护生长因子。此外，最近的全基因组关联研究（GWAS）发现，在尚未明确功能的 TMEM106B 基因内的多个单核苷酸多态性（SNP）与 FTLD-TDP 显著相关，提示 TMEM106B 基因型可增加 FTLD-TDP 发病风险。事实上，与 TMEM106B 基因型相关的 TMEM106B 表达水平可能在疾病发病机制中发挥作用。
由于对 TMEM106B 及其在人脑内的表达知之甚少，我们对来自正常个体、有和无 GRN 基因突变的 FTLD-TDP 个体以及其他神经退行性疾病个体的死后人脑样本进行了 TMEM106B 免疫组化研究。我们发现 TMEM106B 蛋白由神经元、神经胶质细胞和内皮细胞/周细胞在组织病理学上受影响和不受影响的脑区中胞质表达。此外，我们证明 TMEM106B 表达可能在不同神经元亚型之间存在差异。最后，我们发现 TMEM106B 神经元表达在携带 GRN 基因突变的 FTLD-TDP 病例中明显更为紊乱，与正常和疾病对照相比，包括无 GRN 基因突变的 FTLD-TDP 病例。
我们的数据提供了新发现的 FTLD-TDP 相关蛋白 TMEM106B 的初步神经病理学特征。此外，我们证明携带 GRN 基因突变的 FTLD-TDP 病例存在神经元 TMEM106B 亚细胞定位丧失，进一步表明 TMEM106B 和颗粒体蛋白可能在 FTLD-TDP 中具有病理生理学联系。
