跨膜蛋白106B（TMEM106B）水平升高会导致溶酶体功能障碍，进而影响突触信号传导和神经元健康。
Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health.
作者信息
Perneel Jolien, Lastra Osua Miranda, Alidadiani Sara, Peeters Nele, De Witte Linus, Heeman Bavo, Manzella Simona, De Rycke Riet, Brooks Mieu, Perkerson Ralph B, Calus Elke, De Coster Wouter, Neumann Manuela, Mackenzie Ian R A, Van Dam Debby, Asselbergh Bob, Ellender Tommas, Zhou Xiaolai, Rademakers Rosa
机构信息
VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
出版信息
Mol Neurodegener. 2025 Apr 23;20(1):45. doi: 10.1186/s13024-025-00831-2.
BACKGROUND
Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear how TMEM106B modulates disease risk.
METHODS
To study the effect of increased TMEM106B levels, we generated Cre-inducible transgenic mice expressing human wild-type TMEM106B. We evaluated lysosomal and neuronal health using in vitro and in vivo assays including transmission electron microscopy, immunostainings, behavioral testing, electrophysiology, and bulk RNA sequencing.
RESULTS
We created the first transgenic mouse model that successfully overexpresses TMEM106B, with a 4- to 8-fold increase in TMEM106B protein levels in heterozygous (hTMEM106B(+)) and homozygous (hTMEM106B(++)) animals, respectively. We showed that the increase in TMEM106B protein levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Increased TMEM106B levels led to altered synaptic signaling in 12-month-old animals which further exhibited an anxiety-like phenotype. Finally, we observed mild neuronal loss in the hippocampus of 21-month-old animals.
CONCLUSION
Characterization of the first transgenic mouse model that overexpresses TMEM106B suggests that higher levels of TMEM106B negatively impacts brain health by modifying brain aging and impairing the resilience of the brain to the pathomechanisms of neurodegenerative disorders. This novel model will be a valuable tool to study the involvement and contribution of increased TMEM106B levels to aging and will be essential to study the many age-related diseases in which TMEM106B was genetically shown to be a disease- and risk-modifier.
背景
已知跨膜蛋白106B（TMEM106B）的基因变异会影响多种神经退行性疾病的风险和表现，并改变健康衰老过程。虽然人体研究的证据表明风险等位基因与TMEM106B的较高水平相关，但TMEM106B水平升高对神经退行性变和衰老的影响尚未得到评估，并且TMEM106B如何调节疾病风险仍不清楚。
方法
为了研究TMEM106B水平升高的影响，我们构建了表达人野生型TMEM106B的Cre诱导型转基因小鼠。我们使用体外和体内实验评估溶酶体和神经元健康，包括透射电子显微镜、免疫染色、行为测试、电生理学和大量RNA测序。
结果
我们创建了第一个成功过表达TMEM106B的转基因小鼠模型，杂合子（hTMEM106B(+)）和纯合子（hTMEM106B(++)）动物中TMEM106B蛋白水平分别增加了4至8倍。我们表明，TMEM106B蛋白水平的增加诱导了溶酶体功能障碍以及与神经元可塑性、学习和记忆相关基因的年龄相关下调。TMEM106B水平升高导致12个月大的动物突触信号改变，这些动物进一步表现出焦虑样表型。最后，我们在21个月大的动物海马体中观察到轻度神经元丢失。
结论
对第一个过表达TMEM106B的转基因小鼠模型的表征表明，较高水平的TMEM106B通过改变脑衰老和损害大脑对神经退行性疾病发病机制的恢复力，对大脑健康产生负面影响。这个新模型将是研究TMEM106B水平升高对衰老的影响及作用的有价值工具，对于研究许多在基因层面显示TMEM106B是疾病和风险调节因子的与年龄相关疾病至关重要。
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