Chang Michael C, Srinivasan Karpagam, Friedman Brad A, Suto Eric, Modrusan Zora, Lee Wyne P, Kaminker Joshua S, Hansen David V, Sheng Morgan
Department of Neuroscience, Genentech, Inc., South San Francisco, CA
Department of Neuroscience, Genentech, Inc., South San Francisco, CA.
J Exp Med. 2017 Sep 4;214(9):2611-2628. doi: 10.1084/jem.20160999. Epub 2017 Aug 4.
Loss-of-function mutations in cause frontotemporal dementia (FTD) with transactive response DNA-binding protein of 43 kD (TDP-43)-positive inclusions and neuronal ceroid lipofuscinosis (NCL). There are no disease-modifying therapies for either FTD or NCL, in part because of a poor understanding of how mutations in genes such as contribute to disease pathogenesis and neurodegeneration. By studying mice lacking progranulin (PGRN), the protein encoded by , we discovered multiple lines of evidence that PGRN deficiency results in impairment of autophagy, a key cellular degradation pathway. PGRN-deficient mice are sensitive to because of deficits in xenophagy, a specialized form of autophagy that mediates clearance of intracellular pathogens. Cells lacking PGRN display reduced autophagic flux, and pathological forms of TDP-43 typically cleared by autophagy accumulate more rapidly in PGRN-deficient neurons. Our findings implicate autophagy as a novel therapeutic target for -associated NCL and FTD and highlight the emerging theme of defective autophagy in the broader FTD/amyotrophic lateral sclerosis spectrum of neurodegenerative disease.
基因功能丧失突变可导致额颞叶痴呆（FTD），伴有43kD的反式激活反应DNA结合蛋白（TDP - 43）阳性包涵体以及神经元蜡样脂褐质沉积症（NCL）。目前对于FTD或NCL均没有改善疾病的疗法，部分原因是对诸如该基因的突变如何导致疾病发病机制和神经退行性变了解不足。通过研究缺乏颗粒前体蛋白（PGRN，由该基因编码的蛋白质）的小鼠，我们发现了多条证据表明PGRN缺乏会导致自噬受损，自噬是一种关键的细胞降解途径。由于异噬作用（一种介导细胞内病原体清除的自噬特殊形式）存在缺陷，缺乏PGRN的小鼠对感染敏感。缺乏PGRN的细胞自噬通量降低，通常通过自噬清除的病理性TDP - 43形式在缺乏PGRN的神经元中积累得更快。我们的研究结果表明自噬是与该基因相关的NCL和FTD的一个新的治疗靶点，并突出了自噬缺陷在更广泛的FTD/肌萎缩侧索硬化神经退行性疾病谱中这一新兴主题。
