Ward Michael E, Chen Robert, Huang Hsin-Yi, Ludwig Connor, Telpoukhovskaia Maria, Taubes Ali, Boudin Helene, Minami Sakura S, Reichert Meredith, Albrecht Philipp, Gelfand Jeffrey M, Cruz-Herranz Andres, Cordano Christian, Alavi Marcel V, Leslie Shannon, Seeley William W, Miller Bruce L, Bigio Eileen, Mesulam Marek-Marsel, Bogyo Matthew S, Mackenzie Ian R, Staropoli John F, Cotman Susan L, Huang Eric J, Gan Li, Green Ari J
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Transl Med. 2017 Apr 12;9(385). doi: 10.1126/scitranslmed.aah5642.
Heterozygous mutations in the gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous mutation carriers. Lymphoblasts from heterozygous mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in -associated FTD and -associated NCL.
该基因中的杂合突变导致原颗粒蛋白（PGRN）单倍剂量不足，并引发额颞叶痴呆（FTD），这是一种发生于老年人的神经退行性综合征。另一方面，纯合突变会导致PGRN完全缺失，并引发神经元蜡样脂褐质沉积症（NCL），这是一种通常见于儿童的溶酶体贮积病。鉴于FTD和NCL主要的临床和病理特征不同，与PGRN完全缺失和部分缺失相关的疾病机制是相似还是不同，仍存在争议。我们发现，PGRN单倍剂量不足会导致人类出现类似NCL的特征，其中一些特征在痴呆症发作之前就已出现。非侵入性视网膜成像显示，杂合突变携带者存在临床前视网膜脂褐质沉积症。杂合突变携带者的死后皮质中也出现了脂褐质沉积增加和细胞内类似NCL的贮积物质。来自杂合突变携带者的淋巴母细胞积累了大量类似NCL的贮积物质，通过使PGRN表达正常化可挽救这种情况。来自杂合突变携带者的成纤维细胞显示出溶酶体蛋白酶活性受损。我们的研究结果表明，原颗粒蛋白单倍剂量不足会导致人类出现类似NCL的贮积物质积累和早期视网膜异常，并表明溶酶体功能障碍是与相关FTD和相关NCL相关的核心疾病过程。
