Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis in white matter and an accumulation of myelin debris in microglial lysosomes in the same regions. Accumulation of myelin debris is also observed in white matter of patients with GRN-associated FTD. In addition, our findings also suggest that PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Finally, Grn KO mice that are deficient in cathepsin D (Ctsd), a key lysosomal enzyme, have augmented myelin debris and increased neuronal TDP-43 pathology. Together, our data strongly imply that PGRN loss affects microglial activation and lysosomal function, resulting in the accumulation of myelin debris and contributing to TDP-43 pathology.

编码颗粒蛋白前体 ( PGRN ) 的颗粒蛋白前体基因 ( GRN )的功能丧失突变是额颞叶痴呆 (FTD) 的主要原因。GRN相关 FTD 的特征是 TDP-43 包涵体和神经炎症，但 PGRN 损失如何导致疾病仍然难以捉摸。我们表明，Grn敲除 (KO) 小鼠在相同区域的白质中增加了小胶质细胞增生，并在小胶质细胞溶酶体中积累了髓鞘碎片。在与GRN相关的FTD患者的白质中也观察到髓磷脂碎片的积累。此外，我们的研究结果还表明，小胶质细胞中 PGRN 不足会导致溶酶体介导的髓鞘碎片清除受损。最后，格林缺乏组织蛋白酶 D (Ctsd)（一种关键的溶酶体酶）的 KO 小鼠增加了髓鞘碎片并增加了神经元 TDP-43 病理学。总之，我们的数据强烈暗示 PGRN 损失影响小胶质细胞活化和溶酶体功能，导致髓鞘碎片的积累并导致 TDP-43 病理学。