Klein Zoe A, Takahashi Hideyuki, Ma Mengxiao, Stagi Massimiliano, Zhou Melissa, Lam TuKiet T, Strittmatter Stephen M
Program in Cellular Neuroscience, Neurodegeneration & Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; MS & Proteomics Resource, WM Keck Biotechnology Resource Laboratory, New Haven, CT 06511, USA.
Neuron. 2017 Jul 19;95(2):281-296.e6. doi: 10.1016/j.neuron.2017.06.026.
Progranulin (GRN) and TMEM106B are associated with several common neurodegenerative disorders including frontotemporal lobar degeneration (FTLD). A TMEM106B variant modifies GRN-associated FTLD risk. However, their functional relationship in vivo and the mechanisms underlying the risk modification remain unclear. Here, using transcriptomic and proteomic analyses with Grn and Tmem106b mice, we show that, while multiple lysosomal enzymes are increased in Grn brain at both transcriptional and protein levels, TMEM106B deficiency causes reduction in several lysosomal enzymes. Remarkably, Tmem106b deletion from Grn mice normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration without improving lipofuscin, C1q, and microglial accumulation. Mechanistically, TMEM106B binds vacuolar-ATPase accessory protein 1 (AP1). TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing lysosomal protein levels in Grn neurons. Thus, Grn and Tmem106b genes have opposite effects on lysosomal enzyme levels, and their interaction determines the extent of neurodegeneration.
前颗粒蛋白（GRN）和跨膜蛋白106B（TMEM106B）与包括额颞叶痴呆（FTLD）在内的几种常见神经退行性疾病相关。一种TMEM106B变体可改变与GRN相关的FTLD风险。然而，它们在体内的功能关系以及风险改变的潜在机制仍不清楚。在这里，通过对Grn和Tmem106b小鼠进行转录组和蛋白质组分析，我们发现，虽然在Grn小鼠大脑中多种溶酶体酶在转录和蛋白质水平上均增加，但TMEM106B缺乏会导致几种溶酶体酶减少。值得注意的是，从Grn小鼠中删除Tmem106b可使溶酶体蛋白水平正常化，并挽救与FTLD相关的行为异常和视网膜变性，而不会改善脂褐素、C1q和小胶质细胞积聚。从机制上讲，TMEM106B与液泡ATP酶辅助蛋白1（AP1）结合。TMEM106B缺乏会降低液泡ATP酶AP1和V0亚基，损害溶酶体酸化并使Grn神经元中的溶酶体蛋白水平正常化。因此，Grn和Tmem106b基因对溶酶体酶水平具有相反的影响，它们的相互作用决定了神经退行性变的程度。
