Since the initial identification of TMEM106B as a risk factor for frontotemporal lobar degeneration (FTLD), multiple genetic studies have found TMEM106B variants to modulate disease risk in a variety of brain disorders and healthy aging. Neurodegenerative disorders are typically characterized by inclusions of misfolded proteins and since lysosomes are an important site for cellular debris clearance, lysosomal dysfunction has been closely linked to neurodegeneration. Consequently, many causal mutations or genetic risk variants implicated in neurodegenerative diseases encode proteins involved in endosomal–lysosomal function. As an integral lysosomal transmembrane protein, TMEM106B regulates several aspects of lysosomal function and multiple studies have shown that proper TMEM106B protein levels are crucial for maintaining lysosomal health. Yet, the precise function of TMEM106B at the lysosomal membrane is undetermined and it remains unclear how TMEM106B modulates disease risk. Unexpectedly, several independent groups recently showed that the C-terminal domain (AA120-254) of TMEM106B forms amyloid fibrils in the brain of patients with a diverse set of neurodegenerative conditions. The recognition that TMEM106B can form amyloid fibrils and is present across neurodegenerative diseases sheds new light on TMEM106B as a central player in neurodegeneration and brain health, but also raises important new questions. In this review, we summarize current knowledge and place a decade’s worth of TMEM106B research into an exciting new perspective.

自从最初将TMEM106B确定为额颞叶变性 (FTLD) 的危险因素以来，多项遗传研究发现TMEM106B变体来调节各种脑部疾病和健康衰老的疾病风险。神经退行性疾病的典型特征是包含错误折叠的蛋白质，并且由于溶酶体是清除细胞碎片的重要场所，因此溶酶体功能障碍与神经退行性变密切相关。因此，许多与神经退行性疾病有关的因果突变或遗传风险变异编码参与内体-溶酶体功能的蛋白质。作为一种完整的溶酶体跨膜蛋白，TMEM106B 调节溶酶体功能的几个方面，多项研究表明，适当的 TMEM106B 蛋白水平对于维持溶酶体健康至关重要。然而，TMEM106B 在溶酶体膜上的确切功能尚未确定，并且 TMEM106B 如何调节疾病风险仍不清楚。不料，几个独立小组最近表明，TMEM106B 的 C 末端结构域 (AA120-254) 在患有多种神经退行性疾病的患者的大脑中形成淀粉样原纤维。认识到 TMEM106B 可以形成淀粉样蛋白原纤维并存在于神经退行性疾病中，这为 TMEM106B 作为神经退行性和大脑健康的核心参与者提供了新的思路，但也提出了重要的新问题。在这篇综述中，我们总结了当前的知识，并将 TMEM106B 十年的研究价值置于一个令人兴奋的新视角。认识到 TMEM106B 可以形成淀粉样蛋白原纤维并存在于神经退行性疾病中，这为 TMEM106B 作为神经退行性和大脑健康的核心参与者提供了新的思路，但也提出了重要的新问题。在这篇综述中，我们总结了当前的知识，并将 TMEM106B 十年的研究价值置于一个令人兴奋的新视角。认识到 TMEM106B 可以形成淀粉样蛋白原纤维并存在于神经退行性疾病中，这为 TMEM106B 作为神经退行性和大脑健康的核心参与者提供了新的思路，但也提出了重要的新问题。在这篇综述中，我们总结了当前的知识，并将 TMEM106B 十年的研究价值置于一个令人兴奋的新视角。