Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Department of Pharmacology and Chemical Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
Adv Exp Med Biol. 2021;1281:219-242. doi: 10.1007/978-3-030-51140-1_14.
It has been more than a decade since heterozygous loss-of-function mutations in the progranulin gene (GRN) were first identified as an important genetic cause of frontotemporal lobar degeneration (FTLD). Due to the highly diverse biological functions of the progranulin (PGRN) protein, encoded by GRN, multiple possible disease mechanisms have been proposed. Early work focused on the neurotrophic properties of PGRN and its role in the inflammatory response. However, since the discovery of homozygous GRN mutations in patients with a lysosomal storage disorder, investigation into the possible roles of PGRN and its proteolytic cleavage products granulins, in lysosomal function and dysfunction, has taken center stage. In this chapter, we summarize the GRN mutational spectrum and its associated phenotypes followed by an in-depth discussion on the possible disease mechanisms implicated in FTLD-GRN. We conclude with key outstanding questions which urgently require answers to ensure safe and successful therapy development for GRN mutation carriers.
自颗粒蛋白基因 (GRN) 的杂合功能丧失突变首次被确定为额颞叶变性 (FTLD) 的重要遗传原因以来，已经过去了十多年。由于颗粒蛋白 (PGRN) 蛋白的生物学功能高度多样化，GRN 编码的多种可能的疾病机制已被提出。早期的工作集中在 PGRN 的神经营养特性及其在炎症反应中的作用。然而，自从在溶酶体贮积症患者中发现同源 GRN 突变以来，对 PGRN 及其蛋白水解裂解产物颗粒素在溶酶体功能和功能障碍中的可能作用的研究已成为焦点。在本章中，我们总结了 GRN 的突变谱及其相关表型，然后深入讨论了与 FTLD-GRN 相关的可能疾病机制。最后，我们提出了一些关键的悬而未决的问题，这些问题迫切需要答案，以确保为 GRN 突变携带者的安全和成功的治疗开发。
