Riordan Ruben, Saxton Aleen, Han Marina, McMillan Pamela J, Kow Rebecca L, Liachko Nicole F, Kraemer Brian C
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
Alzheimers Dement. 2025 Feb;21(2):e14468. doi: 10.1002/alz.14468. Epub 2024 Dec 23.
Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for several neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD). The C-terminal (CT) domain of TMEM106B occurs as fibrillar protein deposits in the brains of dementia patients.
To determine the TMEM CT aggregation propensity and neurodegenerative potential, we generated transgenic Caenorhabditis elegans expressing the human TMEM CT fragment aggregating in FTLD cases.
Pan-neuronal expression of human TMEM CT in C. elegans causes severe neuronal dysfunction driving neurodegeneration. Cytosolic aggregation of TMEM CT proteins accompanied by behavioral dysfunction and neurodegeneration. Loss of pgrn-1 did not modify TMEM CT phenotypes suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. The mechanistic drivers of TMEM106B proteinopathy appear distinct from known modifiers of tauopathy.
Our data demonstrate that TMEM CT aggregation can kill neurons. TMEM106B transgenic C.elegans provide a useful model for characterizing TMEM106B proteinopathy-mediated neurodegeneration in FTLD.
Pan-neuronal expression of human TMEM106B C-terminal fragments (TMEM CT) in C. elegans neurons drives a suite of disease-related phenotypes useful for modeling the molecular and cellular features of TMEM106B neuropathology. TMEM CT expression results in extensive TMEM aggregation and accumulation of highly detergent insoluble protein species. TMEM CT expression causes moderate to severe neuronal dysfunction dependent on TMEM CT abundance as measured by stereotypical behavioral readouts. TMEM CT expression drives significant neurodegenerative changes. Dendra2 tagged TMEM exhibits similar properties to untagged TMEM allowing ready visualization of the protein. TMEM CT aggregates accumulate adjacent to but not within lysosomes. PGRN loss of function does not impact TMEM CT toxicity. Modifiers of tau and TDP-43 proteinopathies have little impact on TMEM CT-related neurodegenerative phenotypes.
溶酶体和跨膜蛋白106B（TMEM106B）的基因变异会改变多种神经退行性疾病的风险，尤其是额颞叶痴呆（FTLD）。TMEM106B的C末端（CT）结构域在痴呆患者大脑中以纤维状蛋白沉积物的形式出现。
为了确定TMEM CT的聚集倾向和神经退行性潜能，我们构建了表达在FTLD病例中聚集的人TMEM CT片段的转基因秀丽隐杆线虫。
人TMEM CT在秀丽隐杆线虫中的泛神经元表达导致严重的神经元功能障碍并引发神经退行性变。TMEM CT蛋白的胞质聚集伴随着行为功能障碍和神经退行性变。pgrn-1的缺失并未改变TMEM CT的表型，表明TMEM CT聚集发生在PGRN功能丧失的下游。TMEM106B蛋白病的机制驱动因素似乎与已知的tau蛋白病修饰因子不同。
我们的数据表明TMEM CT聚集可杀死神经元。TMEM106B转基因秀丽隐杆线虫为表征FTLD中TMEM106B蛋白病介导的神经退行性变提供了一个有用的模型。
人TMEM106B C末端片段（TMEM CT）在秀丽隐杆线虫神经元中的泛神经元表达驱动了一系列与疾病相关的表型，这些表型有助于模拟TMEM106B神经病理学的分子和细胞特征。TMEM CT表达导致广泛的TMEM聚集和高度去污剂不溶性蛋白物种的积累。通过定型行为读数测量，TMEM CT表达导致中度至重度神经元功能障碍，这取决于TMEM CT的丰度。TMEM CT表达驱动显著的神经退行性变化。Dendra2标记的TMEM表现出与未标记的TMEM相似的特性，便于对该蛋白进行可视化。TMEM CT聚集体在溶酶体附近而非溶酶体内积累。PGRN功能丧失不影响TMEM CT毒性。tau和TDP-43蛋白病的修饰因子对TMEM CT相关的神经退行性表型影响很小。
