Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, P.R. China.
J Neuropathol Exp Neurol. 2019 Sep 1;78(9):844-853. doi: 10.1093/jnen/nlz059.
Heterozygous loss-of-function mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A). PGRN is a highly conserved, secreted glycoprotein and functions in the central nervous system as a key modulator of microglial function. Hence, altered microglial function caused by PGRN deficiency may be tied to the pathogenesis of FTLD-TDP. Our previous studies showed that haploinsufficiency of GRN mutations extends to microglial PGRN expression in the hippocampal CA1 region. In this study, we found that the CA1 sector was associated with less neuronal loss and more frequent TDP-43 inclusions in FTLD-TDP type A cases with GRN mutations than in sporadic cases. In addition, the CA1 region in GRN mutation cases contained more rod-like microglia, which also had reduced PGRN expression. These findings suggest that the profile of TDP-43 inclusions, neuronal number, and microgliosis in the CA1 sector of FTLD-TDP type A cases may be influenced by GRN gene expression status.
GRN 基因杂合性缺失突变导致颗粒体蛋白（PGRN）单倍体不足，并引起伴有 TDP-43 病理类型 A 的额颞叶变性（FTLD-TDP 型 A）。PGRN 是一种高度保守的分泌糖蛋白，在中枢神经系统中作为小胶质细胞功能的关键调节剂发挥作用。因此，PGRN 缺乏引起的小胶质细胞功能改变可能与 FTLD-TDP 的发病机制有关。我们之前的研究表明，GRN 突变的杂合子缺失会扩展到海马 CA1 区的小胶质细胞 PGRN 表达。在这项研究中，我们发现与散发性病例相比，GRN 突变的 FTLD-TDP 型 A 病例的 CA1 区与较少的神经元丢失和更频繁的 TDP-43 包涵体相关。此外，GRN 突变病例的 CA1 区含有更多杆状小胶质细胞，其 PGRN 表达也减少。这些发现表明，FTLD-TDP 型 A 病例 CA1 区的 TDP-43 包涵体、神经元数量和小胶质细胞增生的特征可能受 GRN 基因表达状态的影响。
