PDF(Pubmed)
Abstract：
Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for a diverse range of neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD) with progranulin (PGRN) haplo-insufficiency, although the molecular mechanisms involved are not yet understood. Through advances in cryo-electron microscopy (cryo-EM), homotypic aggregates of the C-Terminal domain of TMEM106B (TMEM CT) were discovered as a previously unidentified cytosolic proteinopathy in the brains of FTLD, Alzheimer\'s disease, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) patients. While it remains unknown what role TMEM CT aggregation plays in neuronal loss, its presence across a range of aging related dementia disorders indicates involvement in multi-proteinopathy driven neurodegeneration. To determine the TMEM CT aggregation propensity and neurodegenerative potential, we characterized a novel transgenic C. elegans model expressing the human TMEM CT fragment constituting the fibrillar core seen in FTLD cases. We found that pan-neuronal expression of human TMEM CT in C. elegans causes neuronal dysfunction as evidenced by behavioral analysis. Cytosolic aggregation of TMEM CT proteins accompanied the behavioral dysfunction driving neurodegeneration, as illustrated by loss of GABAergic neurons. To investigate the molecular mechanisms driving TMEM106B proteinopathy, we explored the impact of PGRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressing C. elegans with loss of pgrn-1, the C. elegans ortholog of human PGRN. Neither full nor partial loss of pgrn-1 altered the motor phenotype of our TMEM CT model suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. We also tested the ability of genetic suppressors of tauopathy to rescue TMEM CT pathology. We found that genetic knockout of spop-1, sut-2, and sut-6 resulted in weak to no rescue of proteinopathy phenotypes, indicating that the mechanistic drivers of TMEM106B proteinopathy may be distinct from tauopathy. Taken together, our data demonstrate that TMEM CT aggregation can kill neurons. Further, expression of TMEM CT in C. elegans neurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease.
摘要：
溶酶体和跨膜蛋白106B（TMEM106B）的遗传变异改变了各种神经退行性疾病的风险，尤其是额颞叶变性（FTLD）伴有颗粒原蛋白（PGRN）单plo功能不全，尽管涉及的分子机制尚未被理解。通过低温电子显微镜(cryo-EM)的发展，TMEM106B（TMEMCT）的C末端结构域的同型聚集体被发现为FTLD大脑中先前未发现的细胞溶质蛋白病，老年痴呆症,进行性核上性麻痹（PSP），路易体痴呆（DLB）患者。虽然尚不清楚TMEMCT聚集在神经元丢失中起什么作用，它在一系列与衰老相关的痴呆疾病中的存在表明参与了多蛋白病驱动的神经变性。为了确定TMEMCT聚集倾向和神经退行性潜能，我们表征了一种新型的转基因秀丽隐杆线虫模型，该模型表达了人TMEMCT片段，该片段构成了FTLD病例中所见的纤维状核心。我们发现，秀丽隐杆线虫中人TMEMCT的泛神经元表达会导致神经元功能障碍，如行为分析所证明的。TMEMCT蛋白的胞浆聚集伴随行为功能障碍驱动神经变性，如GABA能神经元的损失所示。探讨TMEM106B蛋白病的分子机制,我们探讨了PGRN丢失对TMEMCT表达的神经退行性影响。为此,我们产生了表达秀丽隐杆线虫的TMEMCT，缺失pgrn-1，人类PGRN的C.elegans直系同源物。pgrn-1的全部或部分损失均未改变我们的TMEMCT模型的运动表型，表明TMEMCT聚集发生在PGRN功能丧失的下游。我们还测试了tau蛋白病的遗传抑制因子挽救TMEMCT病理学的能力。我们发现spop-1，sut-2和sut-6的基因敲除导致蛋白质病表型的弱至无挽救，表明TMEM106B蛋白病的机制驱动因素可能与tau蛋白病不同。一起来看,我们的数据表明，TMEMCT聚集可以杀死神经元。Further,TMEMCT在C.elegans神经元中的表达为神经退行性疾病中TMEM106B蛋白病的功能表征提供了有用的模型。
