Mishra Swati, Morshed Nader, Sindhu Sonia, Kinoshita Chizuru, Stevens Beth, Jayadev Suman, Young Jessica E
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA.
Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA.
bioRxiv. 2025 Jan 7:2024.06.25.600648. doi: 10.1101/2024.06.25.600648.
The gene encodes the sortilin related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in are causative for Alzheimer's disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains. is highly expressed in the central nervous system, including in microglia, the tissue resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to AD pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1-42 and synaptosomes is increased in SORLA deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired in deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo-lysosomal network as a potential novel pathway through which may increase AD risk and contribute to development of AD. Additionally, our findings may inform development of novel lysosome and microglia associated drug targets for AD.
该基因编码sortilin相关受体蛋白SORLA，这是一种分选受体，可调节多种底物的内溶酶体运输。该基因的功能丧失变体是阿尔茨海默病（AD）的病因，并且在人类AD大脑中反复观察到SORLA表达降低。SORLA在中枢神经系统中高度表达，包括在小胶质细胞（大脑中的组织驻留免疫细胞）中。SORLA的缺失导致人诱导多能干细胞衍生的小胶质样细胞（hMGLs）中的溶酶体增大。然而，SORLA缺乏如何导致小胶质细胞中的溶酶体功能障碍以及这如何导致AD发病机制尚不清楚。在本研究中，我们表明SORLA的缺失导致hMGLs中溶酶体酶的运输改变，从而导致溶酶体降解和溶酶体酶活性降低。在SORLA缺陷的hMGLs中，纤维状淀粉样蛋白β1-42和突触小体的吞噬摄取增加，但由于溶酶体降解减少，这些底物异常积聚在溶酶体中。溶酶体清除的另一种机制，即溶酶体外排，在SORLA缺陷的小胶质细胞中也受损，这可能导致免疫反应改变。总体而言，这些数据表明SORLA在hMGLs中溶酶体水解酶的正确运输中具有重要作用，这对小胶质细胞功能至关重要。这进一步证实了小胶质细胞内溶酶体网络是SORLA可能增加AD风险并促进AD发展的潜在新途径。此外，我们的发现可能为AD的新型溶酶体和小胶质细胞相关药物靶点的开发提供信息。
