Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
Department of Rehabilitation Medicine, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Huashan Hospital, Institute for Translational Brain Research, Fudan University, Shanghai, China.
Mol Neurodegener. 2023 Aug 10;18(1):54. doi: 10.1186/s13024-023-00644-1.
Mutations of the gene TMEM106B are risk factors for diverse neurodegenerative diseases. Previous understanding of the underlying mechanism focused on the impairment of lysosome biogenesis caused by TMEM106B loss-of-function. However, mutations in TMEM106B increase its expression level, thus the molecular process linking these mutations to the apparent disruption in TMEM106B function remains mysterious.
Recent new studies reported that TMEM106B proteins form intracellular amyloid filaments which universally exist in various neurodegenerative diseases, sometimes being the dominant form of protein aggregation. In light of these new findings, in this review we systematically examined previous efforts in understanding the function of TMEM106B in physiological and pathological conditions. We propose that TMEM106B aggregations could recruit normal TMEM106B proteins and interfere with their function.
TMEM106B mutations could lead to lysosome dysfunction by promoting the aggregation of TMEM106B and reducing these aggregations may restore lysosomal function, providing a potential therapeutic target for various neurodegenerative diseases.
TMEM106B 基因突变是多种神经退行性疾病的风险因素。先前对其潜在机制的理解主要集中在 TMEM106B 功能丧失导致溶酶体生物发生受损上。然而，TMEM106B 的突变会增加其表达水平，因此将这些突变与 TMEM106B 功能明显中断联系起来的分子过程仍然是神秘的。
最近的新研究报告称，TMEM106B 蛋白形成细胞内淀粉样纤维，这些纤维普遍存在于各种神经退行性疾病中，有时是蛋白质聚集的主要形式。鉴于这些新发现，在这篇综述中，我们系统地检查了先前在生理和病理条件下理解 TMEM106B 功能的努力。我们提出，TMEM106B 聚集可能会招募正常的 TMEM106B 蛋白并干扰其功能。
TMEM106B 突变可通过促进 TMEM106B 的聚集导致溶酶体功能障碍，减少这些聚集可能恢复溶酶体功能，为各种神经退行性疾病提供潜在的治疗靶点。
