Laboratory of Molecular and Cellular Neuropathology, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.
J Mol Neurosci. 2011 Nov;45(3):561-73. doi: 10.1007/s12031-011-9625-0. Epub 2011 Aug 24.
Loss-of-function mutations in the multifunctional growth factor progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) with TDP-43 protein accumulation. Nuclear TDP-43 protein with key roles in RNA metabolism is also aggregated in amyotrophic lateral sclerosis (ALS), suggesting that ALS and FTLD constitute a broad disease continuum. However, the fact that mutations in GRN are associated with FTLD, while mutations in TDP-43 cause a preferential loss of motor neurons resulting in ALS-end of the disease spectrum, suggests involvement of both cell-autonomous and non-autonomous mechanisms. Studies on animal models and in vitro studies have been instrumental in understanding the link between GRN and TDP-43 and also their role in neurodegeneration. For instance, in mouse models, allelic deficiencies of Grn do not recapitulate human pathology of TDP-43 brain accumulations, but embryonic neurons derived from these mice do show abnormal TDP-43 accumulation after additional cellular challenges, suggesting that TDP-43 changes observed in GRN mutation carriers might also relate to stress. Recent results have shown that the dual action of GRN in growth modulation and inflammation could be due to its negative regulation of TNF-α signaling. In addition, GRN also interacts with sortilin and is endocytosed, thereby regulating its own levels and possibly also modulating the turnover of other proteins including that of TDP-43. Accumulating evidence suggests that TDP-43 abnormal cellular aggregation causes a possible gain of function, also suggested by recently constructed mouse models of TDP-43 proteinopathy; however, it would be inconvincible that sequestration of physiological TDP-43 within cellular aggregates observed in patients would be innocuous for disease pathogenesis. This review discusses some of these data on the possible link between GRN and TDP-43 as well as mechanisms involved in TDP-43-led neurodegeneration. Continued multitiered efforts on genetic, cell biological, and animal modeling approaches would prove crucial in finding a cure for GRN-related diseases.
颗粒体蛋白前体（GRN）的多功能生长因子功能丧失性突变导致伴有 TDP-43 蛋白聚集的额颞叶变性（FTLD）。核 TDP-43 蛋白在 RNA 代谢中起关键作用，也在肌萎缩侧索硬化症（ALS）中聚集，这表明 ALS 和 FTLD 构成了广泛的疾病连续体。然而，GRN 突变与 FTLD 相关，而 TDP-43 突变导致运动神经元的优先丧失，导致 ALS-疾病谱的末端，这表明涉及细胞自主和非自主机制。对动物模型和体外研究的研究有助于理解 GRN 和 TDP-43 之间的联系及其在神经退行性变中的作用。例如，在小鼠模型中，Grn 的等位基因缺乏不能重现 TDP-43 大脑积聚的人类病理学，但这些小鼠衍生的胚胎神经元在额外的细胞挑战后确实显示出异常的 TDP-43 积累，这表明在 GRN 突变携带者中观察到的 TDP-43 变化也可能与应激有关。最近的结果表明，GRN 在生长调节和炎症中的双重作用可能是由于其对 TNF-α信号的负调节。此外，GRN 还与分选蛋白相互作用并被内吞，从而调节其自身水平，并可能调节其他蛋白质（包括 TDP-43）的周转率。越来越多的证据表明，TDP-43 异常细胞聚集导致可能的功能获得，这也被最近构建的 TDP-43 蛋白病的小鼠模型所证实；然而，在患者中观察到的细胞内聚集体中生理 TDP-43 的隔离对于疾病发病机制是否无害还存在争议。本综述讨论了这些关于 GRN 和 TDP-43 之间可能联系的一些数据，以及涉及 TDP-43 导致的神经退行性变的机制。在遗传、细胞生物学和动物建模方法方面的持续多层次努力将证明对于寻找 GRN 相关疾病的治疗方法至关重要。
