Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

中文翻译：

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由于颗粒体蛋白前体突变导致额颞叶痴呆中 β-葡萄糖脑苷脂酶活性和加工受损。


颗粒体蛋白前体 (GRN) 的功能丧失突变是额颞叶痴呆的主要常染色体显性遗传原因。大多数致病性 GRN 突变会导致颗粒体蛋白前体单倍体不足，这被认为会导致 GRN 突变携带者发生额颞叶痴呆。颗粒体蛋白前体单倍体不足可能通过破坏溶酶体功能来驱动额颞叶痴呆的发病机制，因为两个等位基因上有 GRN 突变的患者会出现溶酶体贮积症神经元蜡样质脂褐质沉积症，而有 GRN 突变 (FTD-GRN) 的额颞叶痴呆患者也会积聚脂褐质。颗粒体蛋白前体不足引起的具体溶酶体缺陷尚不清楚，但新出现的数据表明颗粒体蛋白前体不足可能会损害溶酶体鞘脂代谢酶。我们使用荧光活性测定、酶水平和翻译后修饰的生化分​​析以及定量神经病理学研究了颗粒体蛋白前体不足对 FTD-GRN 患者额下回鞘脂代谢酶的影响。在所研究的酶中，只有 β-葡萄糖脑苷脂酶在 FTD-GRN 患者中表现出受损。 FTD-GRN 患者的大脑活动低于对照组，这与成熟 β-葡萄糖脑苷脂酶蛋白水平较低以及不溶性、不完全糖基化 β-葡萄糖脑苷酶的积累有关。免疫染色显示 FTD-GRN 患者神经元 β-葡萄糖脑苷脂酶缺失。为了研究颗粒体蛋白前体不足对神经变性之外的 β-葡萄糖脑苷脂酶的影响，我们研究了颗粒体蛋白前体不足小鼠中的 β-葡萄糖脑苷脂酶活性。 Grn-/- 小鼠的大脑比野生型同窝小鼠的 β-葡萄糖脑苷脂酶活性更低，这一点可以通过 AAV-颗粒体蛋白前体基因治疗得到纠正。这些数据表明，颗粒体蛋白前体不足会损害大脑中的 β-葡萄糖脑苷脂酶活性。这种效应在神经元中最强，可能是由于 β-葡萄糖脑苷脂酶加工受损所致。