Abstract：
Gaucher disease (GD) is caused by biallelic GBA1/Gba1 mutations that encode defective glucocerebrosidase (GCase). Progranulin (PGRN, encoded by GRN/Grn) is a modifier of GCase, but the interplay between PGRN and GCase, specifically GBA1/Gba1 mutations, contributing to GD severity is unclear. Mouse models were developed with various dosages of Gba1 D409V mutation against the PGRN deficiency (Grn-/-) [Grn-/-;Gba1D409V/WT (PG9Vwt), Grn-/-;Gba1D409V/D409V (PG9V), Grn-/-;Gba1D409V/Null (PG9VN)]. Disease progression in those mouse models was characterized by biochemical, pathological, transcriptomic, and neurobehavioral analyses. Compared to PG9Vwt, Grn-/-;Gba1WT/Null and Grn-/- mice that had a higher level of GCase activity and undetectable pathologies, homozygous or hemizygous D409V in PG9V or PG9VN, respectively, resulted in profound inflammation and neurodegeneration. PG9VN mice exhibited much earlier onset, shorter life span, tissue fibrosis, and more severe phenotypes than PG9V mice. Glycosphingolipid accumulation, inflammatory responses, lysosomal-autophagy dysfunction, microgliosis, retinal gliosis, as well as α-Synuclein increases were much more pronounced in PG9VN mice. Neurodegeneration in PG9VN was characterized by activated microglial phagocytosis of impaired neurons and programmed cell death due to necrosis and, possibly, pyroptosis. Brain transcriptomic analyses revealed the intrinsic relationship between D409V dosage, and the degree of altered gene expression related to lysosome dysfunction, microgliosis, and neurodegeneration in GD, suggesting the disease severity is dependent on a GCase activity threshold related to Gba1 D409V dosage and loss of PGRN. These findings contribute to a deeper understanding of GD pathogenesis by elucidating additional underlying mechanisms of interplay between PGRN and Gba1 mutation dosage in modulating GCase function and disease severity in GD and GBA1-associated neurodegenerative diseases.
摘要：
戈谢病(GD)由编码缺陷型葡糖脑苷脂酶(GCase)的双等位基因GBA1/Gba1突变引起。前颗粒蛋白（PGRN，由GRN/Grn编码)是GCase的修饰符，但是PGRN和GCase之间的相互作用，特别是GBA1/GBA1突变，对GD严重程度的影响尚不清楚。用各种剂量的Gba1D409V突变针对PGRN缺陷（Grn-/-）[Grn-/-;Gba1D409V/WT（PG9Vwt），Grn-/-;Gba1D409V/D409V(PG9V),Grn-/-;Gba1D409V/Null(PG9VN)]。这些小鼠模型的疾病进展以生化特征为特征，病态,转录组，和神经行为分析。与PG9Vwt相比，Grn-/-；Gba1WT/Null和Grn-/-小鼠具有较高水平的GCase活性和无法检测的病理，PG9V或PG9VN中的纯合或半合子D409V，分别,导致严重的炎症和神经变性。PG9VN小鼠表现出更早的发病，寿命较短，组织纤维化，和更严重的表型比PG9V小鼠。鞘糖脂积累，炎症反应，溶酶体-自噬功能障碍,小胶质细胞增生,视网膜胶质增生,在PG9VN小鼠中，α-突触核蛋白的增加更为明显。PG9VN中的神经变性的特征在于受损神经元的活化小胶质细胞吞噬作用和由于坏死而导致的程序性细胞死亡，可能,焦亡。脑转录组学分析揭示了D409V剂量之间的内在关系，以及与溶酶体功能障碍相关的基因表达改变的程度，小胶质细胞增生,和GD的神经变性，提示疾病的严重程度取决于GCase活性阈值与Gba1D409V剂量和PGRN丢失相关。这些发现通过阐明PGRN和Gba1突变剂量在调节GD和GBA1相关神经退行性疾病中的GCase功能和疾病严重程度之间的相互作用的其他潜在机制，有助于对GD发病机理的更深入理解。
