The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Hum Mol Genet. 2017 Dec 15;26(24):4861-4872. doi: 10.1093/hmg/ddx364.
Frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders characterized by cognitive and behavioral impairments. Heterozygous mutations in progranulin (PGRN) cause familial FTD and result in decreased PGRN expression, while homozygous mutations result in complete loss of PGRN expression and lead to the neurodegenerative lysosomal storage disorder neuronal ceroid lipofuscinosis (NCL). However, how dose-dependent PGRN mutations contribute to these two different diseases is not well understood. Using iPSC-derived human cortical neurons from FTD patients harboring PGRN mutations, we demonstrate that PGRN mutant neurons exhibit decreased nuclear TDP-43 and increased insoluble TDP-43, as well as enlarged electron-dense vesicles, lipofuscin accumulation, fingerprint-like profiles and granular osmiophilic deposits, suggesting that both FTD and NCL-like pathology are present in PGRN patient neurons as compared to isogenic controls. PGRN mutant neurons also show impaired lysosomal proteolysis and decreased activity of the lysosomal enzyme cathepsin D. Furthermore, we find that PGRN interacts with cathepsin D, and that PGRN increases the activity of cathepsin D but not cathepsins B or L. Finally, we show that granulin E, a cleavage product of PGRN, is sufficient to increase cathepsin D activity. This functional relationship between PGRN and cathepsin D provides a possible explanation for overlapping NCL-like pathology observed in patients with mutations in PGRN or CTSD, the gene encoding cathepsin D. Together, our work identifies PGRN as an activator of lysosomal cathepsin D activity, and suggests that decreased cathepsin D activity due to loss of PGRN contributes to both FTD and NCL pathology in a dose-dependent manner.
额颞叶痴呆（FTD）包括一组以认知和行为障碍为特征的神经退行性疾病。颗粒蛋白前体（PGRN）的杂合突变导致家族性 FTD，并导致 PGRN 表达降低，而纯合突变导致 PGRN 表达完全丧失，并导致神经退行性溶酶体贮积症神经元蜡样脂褐质沉积症（NCL）。然而，剂量依赖性 PGRN 突变如何导致这两种不同的疾病尚不清楚。使用来自携带 PGRN 突变的 FTD 患者的 iPSC 衍生的人类皮质神经元，我们证明 PGRN 突变神经元表现出核 TDP-43 减少和不溶性 TDP-43 增加，以及电子致密小泡增大、脂褐素积累、指纹状特征和颗粒状亲油性沉积物，表明与同基因对照相比，PGRN 患者神经元中存在 FTD 和 NCL 样病理学。PGRN 突变神经元还表现出溶酶体蛋白水解受损和溶酶体酶组织蛋白酶 D 活性降低。此外，我们发现 PGRN 与组织蛋白酶 D 相互作用，PGRN 增加组织蛋白酶 D 的活性但不增加组织蛋白酶 B 或 L 的活性。最后，我们发现 PGRN 的裂解产物 granulin E 足以增加组织蛋白酶 D 的活性。PGRN 和组织蛋白酶 D 之间的这种功能关系为在 PGRN 或编码组织蛋白酶 D 的基因 CTSD 突变患者中观察到的重叠 NCL 样病理学提供了可能的解释。总之，我们的工作确定 PGRN 是溶酶体组织蛋白酶 D 活性的激活剂，并表明由于 PGRN 的丧失导致组织蛋白酶 D 活性降低导致 FTD 和 NCL 病理学以剂量依赖性方式发生。
