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Approaches to develop therapeutics to treat frontotemporal dementia.
Neuropharmacology ( IF 4.7 ) Pub Date : 2020-01-08 , DOI: 10.1016/j.neuropharm.2020.107948
Lisa P Elia 1 , Terry Reisine 2 , Amela Alijagic 1 , Steven Finkbeiner 3
Affiliation  

Frontotemporal degeneration (FTD) is a complex disease presenting as a spectrum of clinical disorders with progressive degeneration of frontal and temporal brain cortices and extensive neuroinflammation that result in personality and behavior changes, and eventually, death. There are currently no effective therapies for FTD. While 60-70% of FTD patients are sporadic cases, the other 30-40% are heritable (familial) cases linked to mutations in several known genes. We focus here on FTD caused by mutations in the GRN gene, which encodes a secreted protein, progranulin (PGRN), that has diverse roles in regulating cell survival, immune responses, and autophagy and lysosome function in the brain. FTD-linked mutations in GRN reduce brain PGRN levels that lead to autophagy and lysosome dysfunction, TDP43 accumulation, excessive microglial activation, astrogliosis, and neuron death through still poorly understood mechanisms. PGRN insufficiency has also been linked to Alzheimer's disease (AD), and so the development of therapeutics for GRN-linked FTD that restore PGRN levels and function may have broader application for other neurodegenerative diseases. This review focuses on a strategy to increase PGRN to functional, healthy levels in the brain by identifying novel genetic and chemical modulators of neuronal PGRN levels. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

中文翻译:

开发治疗额颞叶痴呆的疗法的方法。

额颞变性(FTD)是一种复杂的疾病,表现为一系列临床疾病,包括额叶和颞叶皮质的逐步变性以及广泛的神经炎症,导致人格和行为改变,并最终导致死亡。目前尚无有效的FTD治疗方法。尽管60-70%的FTD患者是散发性病例,其他30-40%是可遗传的(家族性)病例,与几种已知基因的突变有关。我们在这里集中讨论由GRN基因突变引起的FTD,该基因编码一种分泌蛋白,前颗粒蛋白(PGRN),在调节细胞存活,免疫反应以及脑中自噬和溶酶体功能方面具有多种作用。GRN中与FTD相关的突变降低了大脑PGRN水平,导致自噬和溶酶体功能障碍,TDP43积累,小胶质细胞过度活化,星形胶质细胞增多症和神经元死亡的机制尚不清楚。PGRN功能不全也与阿尔茨海默氏病(AD)有关,因此,开发出能够恢复PGRN水平和功能的GRN连锁FTD治疗药物可能会在其他神经退行性疾病中得到更广泛的应用。这篇综述的重点是通过确定神经元PGRN水平的新型遗传和化学调节剂,将PGRN增加到大脑中的功能性,健康水平的策略。本文是名为“对神经退行性疾病的疾病改良疗法的探索”这一特刊的一部分。因此,开发恢复PGRN水平和功能的GRN连锁FTD的疗法可能会在其他神经退行性疾病中得到更广泛的应用。这篇综述的重点是通过确定神经元PGRN水平的新型遗传和化学调节剂,将PGRN增加到大脑中的功能性,健康水平的策略。本文是名为“对神经退行性疾病的疾病改良疗法的探索”这一特刊的一部分。因此,开发恢复PGRN水平和功能的GRN连锁FTD的疗法可能会在其他神经退行性疾病中得到更广泛的应用。这篇综述的重点是通过确定神经元PGRN水平的新型遗传和化学调节剂,将PGRN增加到大脑中的功能性,健康水平的策略。本文是名为“对神经退行性疾病的疾病改良疗法的探索”这一特刊的一部分。
更新日期:2020-01-09
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