Loss-of-function mutations in GRN 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 GRN contribute to disease pathogenesis and neurodegeneration. By studying mice lacking progranulin (PGRN), the protein encoded by GRN, 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 Listeria monocytogenes 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 GRN-associated NCL and FTD and highlight the emerging theme of defective autophagy in the broader FTD/amyotrophic lateral sclerosis spectrum of neurodegenerative disease.

GRN的功能丧失突变导致额颞叶痴呆（FTD），其反应性DNA结合蛋白为43 kD（TDP-43）阳性包涵体，并伴有神经元类脂褐质沉着病（NCL）。没有针对FTD或NCL的疾病缓解疗法，部分原因是人们对GRN等基因突变如何导致疾病的发病机制和神经退行性疾病了解甚少。通过研究缺少前颗粒蛋白（PGRN）（由GRN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，这是关键的细胞降解途径。PGRN缺陷小鼠对单核细胞增生李斯特菌敏感由于异种吞噬的缺陷，异种吞噬是介导细胞内病原体清除的一种特殊形式的自噬。缺乏PGRN的细胞显示出自噬通量减少，并且通常通过自噬清除的TDP-43病理形式在PGRN缺乏的神经元中积累得更快。我们的发现暗示自噬是GRN相关的NCL和FTD的新型治疗靶点，并突出了神经退行性疾病的更广泛的FTD /肌萎缩性侧索硬化频谱中自噬缺陷的新兴主题。