Takahashi Hideyuki, Strittmatter Stephen M
Cellular Neuroscience, Neurodegeneration, Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT, 06536, USA.
Mol Neurodegener. 2025 Jul 26;20(1):86. doi: 10.1186/s13024-025-00873-6.
Although different neurodegenerative diseases are defined by distinct pathological proteins, they share many common features including protein aggregation. Despite this commonality, most current therapeutic approaches in the field, such as anti-aggregate antibodies, are focused on individual diseases or single neuropathologies with only limited success. The endolysosomal proteins progranulin and TMEM106B were both initially associated with frontotemporal lobar degeneration but have subsequently also been linked to other neurodegenerative diseases. Thus, these proteins are predicted to participate in common pathogenic pathways shared across various neurodegenerative diseases. Importantly, recent discoveries of TMEM106B amyloid fibrils in varied neurodegenerative diseases and glycosphingolipid regulation by progranulin and TMEM106B further support their central roles in cross-disease neurodegenerative mechanisms. This review summarizes recent advances in progranulin and TMEM106B function within the endolysosomal system and neurodegenerative diseases. It describes preclinical models and therapeutic approaches for progranulin- and TMEM106B-associated diseases. We also discuss future direction leading to novel alternative therapies targeting shared mechanisms in neurodegenerative diseases.
尽管不同的神经退行性疾病由不同的病理性蛋白质所定义，但它们具有许多共同特征，包括蛋白质聚集。尽管存在这种共性，但该领域目前的大多数治疗方法，如抗聚集抗体，都集中在个别疾病或单一神经病理学上，仅取得了有限的成功。内溶酶体蛋白原颗粒蛋白和跨膜蛋白106B最初都与额颞叶痴呆相关，但随后也与其他神经退行性疾病有关。因此，预计这些蛋白质参与了各种神经退行性疾病共有的常见致病途径。重要的是，最近在多种神经退行性疾病中发现了跨膜蛋白106B淀粉样原纤维，以及原颗粒蛋白和跨膜蛋白106B对糖鞘脂的调节，进一步支持了它们在跨疾病神经退行性机制中的核心作用。这篇综述总结了原颗粒蛋白和跨膜蛋白106B在内溶酶体系统和神经退行性疾病中的功能的最新进展。它描述了与原颗粒蛋白和跨膜蛋白106B相关疾病的临床前模型和治疗方法。我们还讨论了针对神经退行性疾病共享机制的新型替代疗法的未来方向。
