斯坦福大学Monther Abu-Remaileh课题组在研究中取得进展。他们探明了脑溶酶体细胞型分解蛋白图谱确定slc45a1相关疾病为溶酶体疾病。2026年1月22日出版的《细胞》杂志发表了这项成果。
课题组报告了单主题神经元、星形胶质细胞、少突胶质细胞和小胶质细胞溶酶体的定量蛋白图谱。该课题组研究人员鉴定了几十种以前未被注释为溶酶体的蛋白质，并揭示了不同脑细胞类型溶酶体组成的多样性。值得注意的是，该研究组发现SLC45A1是一种神经元特异性溶酶体蛋白，该基因的突变与单基因神经疾病有关。体外和体内SLC45A1羧酶溶酶体功能障碍的丧失。SLC45A1作为溶酶体糖转运体，影响液泡ATP酶（V-ATP酶）V1亚基的稳定性。SLC45A1缺失会降低溶酶体V1亚基，升高溶酶体pH值，破坏铁稳态，导致线粒体功能障碍。总之，他们的工作将slc45a1相关疾病重新定义为LSD，并建立了一个全面的图谱，以细胞类型分辨率研究溶酶体生物学。
据悉，溶酶体基因突变、神经退行性变性和神经性溶酶体贮积症（lsd）。尽管溶酶体在大脑稳态中起着重要作用，但对其细胞类型特异性组成和功能的了解仍然很少。
附：英文原文
Title: Cell-type resolved protein atlas of brain lysosomes identifies SLC45A1-associated disease as a lysosomal disorder
Author: Ali Ghoochani, Julia C. Heiby, Eshaan S. Rawat, Uche N. Medoh, Domenico Di Fraia, Wentao Dong, Marc Gastou, Mohit Rastogi, Vincent Hernandez, Kwamina Nyame, Nouf N. Laqtom, William Durso, Christina Valkova, Alina Isakova, Christoph Kaether, Marius Wernig, Natalia Gomez-Ospina, Christian Franke, Alessandro Ori, Monther Abu-Remaileh
Issue&Volume: 2026-01-22
Abstract: Mutations in lysosomal genes cause neurodegeneration and neuronopathic lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of lysosomes from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of proteins not previously annotated as lysosomal and reveal the diversity of lysosomal composition across brain cell types. Notably, we identified SLC45A1, a gene whose mutations cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. SLC45A1 functions as a lysosomal sugar transporter and impacts the stability of the V1 subunits of the vacuolar ATPase (V-ATPase). Consistently, SLC45A1 loss reduces lysosomal V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis, causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as an LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution.
DOI: 10.1016/j.cell.2025.12.012
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01425-4