From the Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
J Neuropathol Exp Neurol. 2021 Jun 4;80(6):530-540. doi: 10.1093/jnen/nlab040.
Abnormal protein accumulation and mislocalization is a general hallmark of Alzheimer disease. Recent data suggest nucleocytoplasmic transport may be compromised by tau in Alzheimer disease. In this context, we have examined the RNA polymerase II subunit RPB1, which is the catalytic subunit that plays a critical role in transcription. Using immunofluorescence staining in control and Alzheimer disease hippocampal tissue, we show that 2 phosphoisoforms of RPB1 mislocalize from the nucleus to the cytoplasm of neurons in Alzheimer disease. The number of neurons with this cytoplasmic mislocalization is correlated with the burden of pathologic tau (AT8-immunopositive neurons). In order to test whether there is a causal relationship between pathologic tau and cytoplasmic RPB1 accumulation, we used the rTg4510 mouse model, which expresses a regulatable pathologic human tau species harboring the P301L mutation. Using immunofluorescence staining on brain tissue from young (2.5-month-old) and aged (8.5- to 10-month-old) rTg4510 mice, we found a tau- and age-dependent increase in cytoplasmic mislocalization of Rpb1. In summary, this study provides evidence that tau induces mislocalization of RPB1 in Alzheimer disease, and since RPB1 is essential for transcription, this raises the possibility that RPB1 mislocalization could lead to fundamental alterations in neuronal health.
异常蛋白质的积累和定位异常是阿尔茨海默病的一个普遍特征。最近的数据表明，核质转运可能因阿尔茨海默病中的 tau 而受损。在这种情况下，我们研究了 RNA 聚合酶 II 亚基 RPB1，它是在转录中起关键作用的催化亚基。我们使用对照和阿尔茨海默病海马组织中的免疫荧光染色，表明 RPB1 的 2 种磷酸化异构体从细胞核易位到阿尔茨海默病神经元的细胞质中。具有这种细胞质易位的神经元数量与病理 tau（AT8 免疫阳性神经元）的负担相关。为了测试病理 tau 和细胞质 RPB1 积累之间是否存在因果关系，我们使用了 rTg4510 小鼠模型，该模型表达了一种可调节的携带 P301L 突变的病理性人类 tau 种系。我们使用免疫荧光染色对来自年轻（2.5 个月大）和老年（8.5 至 10 个月大）rTg4510 小鼠的脑组织进行研究，发现 Rpb1 的细胞质易位与 tau 和年龄相关。总之，这项研究提供了证据表明 tau 诱导阿尔茨海默病中 RPB1 的定位异常，并且由于 RPB1 对于转录是必需的，这就提出了 RPB1 定位异常可能导致神经元健康的根本改变的可能性。
