Neurodegenerative Brain Diseases, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Neurodegenerative Brain Diseases, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
Trends Mol Med. 2017 Oct;23(10):962-979. doi: 10.1016/j.molmed.2017.08.004. Epub 2017 Sep 7.
Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies.
人类颗粒体蛋白基因（GRN）杂合功能丧失（LOF）突变通过杂合子不足的机制导致额颞叶变性（FTLD）。患者最常表现为额颞痴呆，这是年轻患者中第二常见的神经退行性痴呆。目前，这些患者没有有效的治疗方法。刺激 GRN 蛋白表达或抑制其降解是一种明显的治疗策略，也是当前临床前研究和临床试验的重点。多项研究表明，携带 GRN LOF 突变的患者在临床表现和发病年龄方面存在异质性。最近，这种异质性为鉴定疾病修饰因子提供了机会，因为这些因子可能成为开发疾病修饰或延缓疾病进展治疗方法的合适靶点。
